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Monogamy, Sexual & Parent Behavior, Social Attachment, Oxytocin, Sex Hormones, Childhood Psychosis


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

Devanand Manoli 7:17

Sure. So my name is David Ollie, I'm an assistant professor in the Department of Psychiatry and Behavioral Sciences at UCSF. I'm mostly a basic neuroscientist and my lab works on the neural mechanisms underlying social attachment, everything from sort of the basic molecular biology at the individual cellular level for groups of neurons involved in how we build social memories, up to how these circuits function to guide behavior. I'm also a child psychiatrist and my sort of clinical area of specialty is in early psychosis and understanding social deficits that can occur in the context of a number of neurodevelopmental syndromes, but also how they may influence or potentially even predict the onset of psychiatric disorders later in adolescence or in adulthood. Yeah, I think that probably covers


Nick Jikomes 8:11

all right, so So you're you're a psychiatrist, you actually see human patients, you also run a basic neuroscience research lab. Is that a mouse lab? What kind of animals do you study,


Devanand Manoli 8:21

so we use a mouse like rodent called the prairie vole, that's just about the size of a hamster. So it's a little bit bigger than the sort of average laboratory mouse. And the special thing about variables is that they're in the sort of three to 5% of mammals that are what we call socially monogamous. And so what that means is that these animals form lifelong bonds between mates. And that this is something that endures throughout the throughout adulthood. And another correlate to that is that in addition to actually wanting to spend time with each other, there's a really profound change in their behavior with regards to other potential mates and that they completely reject novel potential. So you can imagine there's lots of interesting both neurobiology as well as behavioral biology, about how these sorts of adaptations to social behavior have evolved, how they occur in the brain. And then one of the other sort of sort of convergences between sort of my clinical interests and our basic science lab is how are these actually influenced by either the genetics associated with neuropsychiatric illnesses or early life experience? How does that either facilitate, you know, sort of stronger relationships later in life? Or how does that actually disrupt the formation of these, you know, when these animals grow up, or you're talking about people in the context of early life experience?


Nick Jikomes 9:40

Yeah, I definitely have a lot I want to dig into with respect to the prairie voles, because the really interesting and they're also sort of a less commonly studied lab animal. So there's really a lot of interesting stuff to dig in there. Before we get to that I wanted to just sort of set things up with some really basic questions. So you know, and As a neuroscientist, and a neuro pathologist, someone who studies animal behavior, can you just define for everyone? How someone like you would define animal behavior in general and social behavior in particular?


Devanand Manoli 10:13

So I think the general term animal behavior is really sort of any observational pattern of activity, at the sort of fine scale level, when we're talking about, you know, sort of simple sequences of movements that sort of comprise what we would call a behavioral sequence to large scale interactions, you know, how does an animal respond to a specific change in its environment to a specific stimulus. So that might contrast sort of spontaneous versus evoked behavior at a very, very macroscopic level? And then when we go into the realm of social behavior, I think at the most liberal definition, it's really how do animals interact with each other, whether we're talking about what we call conspecifics of members of the same species, or, for example, if you were to take an animal, and it's predator, or an animal and its prey, interspecific interactions, and I think all of those really form sort of this context of social behavior. And maybe if it's okay, for the purposes of that conversation, we can say social behavior is largely sort of restricted for the purpose of the conversation to within the species. But I think, especially when it comes to attachment, and and this may be a direction we go, and, you know, there's really interesting intersections between how animals attach to each other, and for example, with certain animals that we come to love in our homes, how they attach to other members or members of other species.


Nick Jikomes 11:25

Yeah, no, I can relate to that. I'm actually at my grandma's house right now. And, and so there's a new puppy here. And so we all know how that goes. You went where I was going, right? Yeah. Well, you, you actually, you actually wrote, I think you wrote like a news and views for a recent study. And you gave, you're talking about like the context dependence of behavior in our behavior, our behavioral tendencies change throughout our lifespan, there's developmental processes that go on when certain things happen to us, you know, we go through puberty, or we have babies, or whatever our behavior patterns can change. And I think you actually use the example of female elephants to sort of talk about how behavior can really change in quite dramatic ways. Depending on the external and the internal context of the animal. Can you maybe talk about the elephant example a little bit just to give people to get people thinking about how behavior changes across the lifespan and in different contexts.


Devanand Manoli 12:20

So I mean, I think that, you know, really, that sort of reflects sort of how hormonal states, for example, or different external stimuli, change the state of the animal. And so you can imagine that if we're talking about sort of a fear response, you're going to have a very, very different set of behaviors in the same context than if you're talking about, for example, the display of aggression behaved in the context of territoriality. Or if we're talking about nurturing behavior, right? If we're talking about a mother, nurturing, its young, versus a mother defending its young against a threat, right. And so in the context of each of those sort of defensive behaviors, you're actually sort of seeing similar patterns of behaviors displayed in different ways and in different contexts, that are really dependent upon the context of the animal that's both sort of influenced by external stimuli, but sort of encoded from the internal state of the animal.


Nick Jikomes 13:15

And so like, when we think about, you know, everyone can think of examples in their lives of like, when their behavior changes, for like, purely internal reasons, right? So you can imagine, you know, we all have examples in our own lives, where, you know, we're in the same basic context that you know, time point A in our life, and then at time point B, we're in that context again, but our behavioral response is very, very different. One of the, you know, one of the things that sort of precipitate, some of these changes are all of the hormonal and neural changes that come with, you know, the onset of puberty and becoming sexually mature. Another one is, you know, having children or when an animal has babies, so what, you know, how do we start to think about what's driving those changes, things like, you know, sex hormones, and other factors that are circulating throughout the body, and how it is that they actually start to change behavior.


Devanand Manoli 14:06

So I think in the context of sex hormones, there's actually it's worth taking a little bit of step back in terms of how we think about the actions of sex hormones on the brain. So the general sort of model, especially when we're talking about mammals, for example, is what we call the sort of organization and activation model and the organization. Part of it is very, very early on. And you know, for primates, it could be actually even intra uterine, probably also for some very, very small aspects of rodent development. But then very early on, you have hormones that differ right between males and females in different ways. And as a consequence of that those hormones have actions in the brain and where those actions generally occur, or where there are specific receptors for these hormones. For example, testosterone, estrogen, right they have individual types of receptors that are in not everywhere in the brain, but in specific regions. And so they have developmental consequences, they can wire the brain differently or at least change the physiology or even the number of neurons in different parts of the brain. In general, when we're thinking about the sort of innate behaviors, we think of the hypothalamus, or like sort of the the most sort of basal reptilian brain, as it were, that are the most dimorphic are the most different between males and females, and they're organized during this early developmental period. But then there's generally a period where it kind of the hormones aren't around. And this is sort of pre puberty, and then the beginning of puberty, we start to see these hormones come up. And that's where this sort of activation sort of aspect of the model comes into play. That, you know, not only are these these circuits now different from a developmental standpoint, but then they're sort of primed or activated, to elicit or to at least potentiate different types of behaviors. And an important feature is that there's probably a lot of wiring that is involved in the behaviors that, for example, differ between males and females that are common, and that there's certain subsets of neurons that are really different influenced the probability or the likelihood of displaying one or the other. But for the most part, both animals have a species if we're talking in general, all mammals can do the same sorts of things. They just do it in different contexts. And so that's where the really big difference when it comes to adult social behaviors really manifests. You know, what is the difference between when a female mouse or a mammal experiences estrus, and then is induced to be reproductively receptive, versus, for example, a male who then has testosterone is induced to mate with the sort of typical displays of mating behavior that they insist that they engage in.


Nick Jikomes 16:38

And can you talk a little bit more about, you know, what most people think of as the two main sex hormones testosterone and estrogen, and in particular, you know, the way that people talk about these, outside of, you know, technical fields is, testosterone is the male hormone estrogen is the female hormone. To what extent is that an oversimplification? And where do these hormones come from? How many of them are produced solely by in the gonads, and to what extent are some of these things actually made and deployed within the brain itself?


Devanand Manoli 17:09

So this, I think that I'll go to your first point about, you know, the difference between testosterone and estrogen. And so basically, testosterone is a precursor to estrogen. And so the simplification of testosterone, male estrogen, female is an oversimplification in a number of different ways. And I'm going to focus just more on the sort of behavioral or the neurobiological component. And there's going to be an important distinction between what potentially is happening in primates, versus what we sort of elucidated happens, for example, in mice. But what we found or the field found is that estrogen is actually one of the principal masculinized features of the road and brain early in development. And what happens is that estrogen is testosterone is produced, and it is locally changed into estrogen in different parts of the brain, there's a specific enzyme that does this, that is also very, very restricted. And by virtue of that circulating testosterone enters the brain becomes estrogen. And then estrogen works on different parts of the male brain to masculinize it in females, there really isn't circulating estrogen, there's not circulating testosterone, because they don't have male gonads. And so there's, in general, what we would say sort of a default differentiation there, you know, that's a very, very gross oversimplification. But there is a pathway that happens in the absence of this sort of early estrogen signaling, that is sort of the differentiation of the female brain. And so it was very paradoxical when sort of researchers were trying to manipulate these neurons, or at least these hormones and actually identified that males that don't respond to estrogen genetically, actually, were D masculinized. And that sort of gave rise to this aromatase aromatization hypothesis of how estrogen is actually the the masculinizing compound. Now in primates, there's a little bit more of a difference that happens in terms of how things are occurring in utero. There's also an expansion of the number of neurons and the types of neurons that respond to androgen or testosterone via the androgen receptor. And so there's probably a little bit more Not surprisingly, more nuanced differentiation, both of males and females for primates.


Nick Jikomes 19:16

I see. So so the reason we can't really just think of testosterone equals male estrogen equals female, is because even in males, when you have testosterone circulating throughout the blood, it goes into the brain, but then in very specific locations, that sounds like you can, in some, in some parts, in some cases, turn that testosterone into estrogen and it's actually having a masculinizing effect, you know, making the circuits more male typical or


Devanand Manoli 19:41

whatever, male, typical, right? And actually, another important thing that is sort of happening at the same time is that actual process is what actually induces the expression for testosterone, they have the receptor for testosterone, parts of the brain. So estrogen really starts first and then there's this whole pathway that it then sort of potentiate Is this sort of cycle of differentiation by virtue of pausing more places to respond to testosterone?


Nick Jikomes 20:06

I see. So you can have the induction of testosterone receptors by estrogen itself, which then subsequently makes new neurons and new circuits responsive to testosterone later on.


Devanand Manoli 20:15

Exactly. And you can imagine with this sort of very nuanced sort of genetic programming, in primates, which have a lot more differentiation happening in utero, right, you have actually access to different hormonal surges. And so that balance gets spread out over a much larger period of time. And there's more complicated nuances because of sort of the genetic interactions between estrogen and testosterone signaling in different parts of the brain.


Nick Jikomes 20:39

And so, you know, for, you know, I guess for for mammals on average, I guess one question would be like, how general are some of these things? How species specific? Are they? The difference between males and females? One way to characterize that would it sounds like is, there's a different pattern of waxing and waning of the sex hormones at at different phases of development? Is that how we can start to think about it?


Devanand Manoli 21:03

So I think that, I would say that that's sort of maybe the the conductor, for sort of these processes that to a certain extent, you know, there's part of the score that's been written by the same players earlier on, and then the the phases of the hormones sort of say, okay, what are we going to do in terms of, you know, differentiating the score, versus what are we going to do in terms of how it's going to play out, right, so you have these early players, that sort of, again, this organization, and then depending upon whether you've differentiated in a more male, typical or female, typical way, how the hormones influence what's happening in sort of adulthood, or adolescence, then that's dictated by these fluctuations. And as you sort of alluded to, even the hormones themselves have different patterns of fluctuations, right, the, the sort of the estrogen, or the estrus hormones go through their own cycle, versus testosterone in males tends to have a much more frequent higher frequency of cycling.


Nick Jikomes 21:55

Interesting, and, to me, one of the keys so far is that the pattern of hormonal flux across development actually sets up how sensitive circuits will be to some of these hormones later on. And so I would imagine, there's some pretty big developmental effects there where, you know, if something happens, or doesn't happen at one phase of development, it's then necessarily going to cause some later phase to change, right things manifest.


Devanand Manoli 22:21

So the metaphor that's often used is that it sets up the sort of genomic landscape, or, you know, it regulates different parts of the genome to then be responsive to these later hormone searches, right, because these receptors that we're talking about actually act on DNA once they bind these hormones. So they're what we call transcription factors. And they dictate both changes in gene expression, but also changes in overall genomic structure. So you know, places that respond to a hormone early, then are primed to either respond or not respond to hormones in a specific way later on in life. And so that also dictates not only have neurons functions, but how genes actually are induced or repressed in response to the hormones and adults.


Nick Jikomes 23:01

I see. So when we're thinking about the effects of sex hormones on behavior, and how that happens at the molecular level hormones actually get into the brain physically go inside of neurons, and they change, you know, jeans coming on and off, and all that stuff.


Devanand Manoli 23:14

Yeah. And then the one actual tweak to all of this is that, for example, with estrogen, just to make things even more complicated, there's even a receptor that's not one of these transcription factors. That's, you know, for example, at the surface of a cell, that actually changes the physiology of cells in response to estrogen. So there's many, many timescales in which these hormones are affecting a lot of different processes that sort of dictate how a neuron is going to function or respond to other stimuli.


Nick Jikomes 23:41

Interesting, and how, how sensitive are patterns of hormone flux to like environmental inputs, you know, what the animal is doing? And what's happening to it at different phases of development?


Devanand Manoli 23:51

So it really depends on sort of what are the mechanisms that are transfer, transferring those signals from the environment into the brain, right? So there are certain hormones, for example, like the ones that, you know, eventually, I think, will lead to like oxytocin and vasopressin that operate on potentially larger timescales, although they have effects in neurons, very acutely, you know, and that, that influences sort of the timescale of their responsiveness. But for example, when we're talking about the steroid hormones, the sex, steroid hormones, they have actually overlap directly in terms of some of their receptors with stress hormones, like the glucocorticoids. And so those are operating now in a timescale, where we're dramatically influencing patterns of gene expression that aren't happening effects or the millisecond timescale, but over, you know, minutes, hours days, you know, even longer than that. And so you can imagine, depending upon the developmental context, for example, for talking these early developmental stages, if there's higher levels of stress hormones that are influencing how the steroid hormones can actually even get access to parts of the genome that can have a very, very dramatic effect that has developed Mental consequences long term, right? Versus, for example, later in life, there are stress hormones, obviously, like glucocorticoids. But there are other pathways that influence the dynamics that these circuits can actually respond to, or how they're responding to other stimuli, whether they're sex hormones or other signals.


Nick Jikomes 25:18

Yeah, it would seem obvious then that, you know, depending on what happens to you, during development, for example, if you have relatively high levels of stressors versus low levels of stressors, all of these things are going to interact. And they're probably going to have like cascading effects on how, you know, subsequent sexual behavior, social behavior, anxiety levels, and you know, almost everything you can think of will will sort of manifest later in life.


Devanand Manoli 25:42

That that's all that's perfectly articulated. That's exactly and that's one of the things that we're very interested in, in particular, how it influences sort of the social and attachment aspects, because, you know, I think we know as people, but also, there's lots and lots of animal literature that those early experiences have very reproducible and profound effects. So the question is, how does that actually happen at a sort of molecular and circuit level?


Nick Jikomes 26:05

And you mentioned earlier, that you studied prairie voles, and hugely, I don't think everyone knows this, but I think there's probably a good general sense out there that, obviously, not all animals are monogamous. There's a range of sort of promiscuity with which animals display sexual interactions with conspecifics, with members of their same species. Some are very promiscuous, and they sort of made and there's no real attachment that forms between the male and the female beyond that, and then, you know, humans, a prairie voles, I think would be, you know, sort of one extreme where we're much more monogamous than the majority of other species. Well, there's that number that you cited for how frequently non monogamy is in the animal kingdom.


Devanand Manoli 26:45

So that that's actually those are, I mean, the earliest estimates were from a researcher named Deborah climbin, who worked late 70s basically estimated about three to 5% of mammals. But even within mammals, right, there's a huge diversity. So as you mentioned, you know, with primates, there's there's a slightly higher than average than sort of across mammals average of monogamous mating systems. But if we go, for example, to canids, right, there's actually like a, I think, probably now three or four year old, sort of studies, let's review, where in the wild with the exception of domesticated dogs, you do not see canine species that don't display some form of social monogamy, you know, sort of independent of their complex social structure. If we go to like songbirds, outside of mammals, 90% of songbirds are monogamous. And so there's huge variability in terms of both just sort of the patterns of meeting systems, and then also the sort of the likelihood that a species is going to actually display those types of behaviors.


Nick Jikomes 27:45

And when we say monogamy, I'm curious to have you define what exactly that means in two respects. So one, when we're talking about sexual behavior, does monogamy mean lifelong pair bonding? Does it mean for a season or like some quote unquote, long period of time? And then does this only refer to sexual behavior? Can we talk about social monogamy in a more general way?


Devanand Manoli 28:04

So I think maybe for the purpose of the conversation, I would sort of veer into the realm of social monogamy, right? Because in most systems, you see that if you really look at the patterns of behavior, you see sort of what we'd say, extra pair meetings, right. And they happen with different frequencies in different contexts. They're actually influenced by different environmental contexts. And so, in general, we're talking about sort of the social monogamy that's displayed by a mating pair. And as you sort of alluded to, there are certain species where it's lifelong. And then there are other species where it's basically a reproductive cycle. And and that varies, you know, again, the frequency and the sort of the styles sort of vary across different subsets of species, you know, presumably based off of sort of the evolutionary pressures that that it's evolved in?


Nick Jikomes 28:55

Yeah, I mean, that's actually an interesting question is, Do we know anything about what some of those evolutionary drivers are? Like? Why would some species, you know, want to be monogamous and not others?


Devanand Manoli 29:05

Sure. So that's a great question. And I think it's maybe useful to kind of divide it at least when we think about mammals, sort of rodents are presented as a primates and sort of what we call below of primates, and then primates and above and you know, canids and dogs, you know, there may be a separate entity. For most species, that largest driving force seems to be sort of female distribution as a consequence of resource scarcity. If you take sort of the so, you know, I think the most recent estimates are at least in mammals, maybe 66. Sick, but 60 times that monogamy has evolved. And if you look at that pattern, you'd seem to have a species that gets distributed over a large territory, where resources aren't necessarily abundant, either seasonally, or you know, sort of just geographically. So then, you know, if you're taking a promiscuous species, the females are sort of left with, you know, raising their young and then having to sort of defend against, you know, intruders defending against, you know, predators, things like that. And so in that context, there is sort of this evolutionary question that, you know, it's influenced by the female, certainly in terms of her wanting to keep a male around. But then the male deciding, is it better for me to risk my offspring with this female being killed or dying versus defending them and co parenting, because that's also a really important feature that sort of CO evolved is that in almost every of these mammalian species, you see very strong co parenting behavior, even though they are independent. And so that sort of sort of evolutionary toss up seems to be one of the major major motivating factors for most mammals that, you know, it's in the male's best interest genetically, as well as, you know, sort of resource provision wise to defend his offspring and his mate against, you know, other potential needs. And I see,


Nick Jikomes 30:50

so we think about this in terms of like David Attenborough nature documentaries, you know, you see something like, you know, the mother bear, and she raises the Cubs by herself. And she's, I guess, basically, what you're saying is, the reason for that is, the bears, as one example, live in environments where the mother is able to get more or less everything she needs, food wise, etc, for the Cubs, and there's really no need for having that second parent there. But other species, I guess, humans would be an example, if we live in more difficult environments, where food is more scarce, you need to have, you know, both parents either partitioning what they're doing to help you're the young and have one or both of them being sort of the ones going out into this sort of more sparse environment and bringing things back so that you have everything you need for the offspring. Yeah.


Devanand Manoli 31:38

And I think that actually may be part of why there's this distinction between sort of primates and below and primates above is that with primates that are like altricial, right, that the young are so so helpless, when they're born, you really need a lot of resources to provide for them for their survival. There's also an another interesting sort of potential correlate, which is that in many, many sort of sort of primate species, or even, you know, if we again, go back to the Kennedys, you also have multigenerational sort of sets of animals living together. And so there's a much more complicated in some cases that are gonna say that this is something that defines the rule. So there's a lot more complex social interactions that are mediating sort of who is mating with whom, who can mate with whom, but more importantly, who lives with whom, and who protects and shares resources. And so you get a much more complex structure where there is at least modeling wise, a benefit to sort of having a single meeting unit, that then sort of creates an intergenerational sort of kinship per family unit. And then depending upon how animals leave, that eventually, that sort of, sort of helps facilitate them forming their own clan, one, you know, with its own numbers and its own sort of ability to provide, again, there's a little bit of a debate between how that really influences and whether that's, you know, cause or consequence. And I should also just add that, you know, another factor that comes into, at least to the models of for primates, is this idea of infanticide, right that, you know, where are you at, and certain people sort of have data sported other, you know, there's contention, that where you have species that may also demonstrate infanticide, as a consequence, potentially, of either genetics or resource scarcity, that actually then also facilitates that even more than need for sort of by parental care to the offspring, sort of Yeah,


Nick Jikomes 33:26

I see. So I mean, again, using the David Attenborough method of coming up with examples here, you know, I've seen many nature documentaries, where you have a pride of lions, right? There's, there's sort of the dominant male, and he effectively has a harem of females, eventually, he gets old and feeble enough, and a younger male will come and sort of take over the pride. And, you know, one of the dark aspects for that species is the very often My understanding is that the new male will basically murder all of the infants.


Devanand Manoli 33:55

Right, right. And interestingly, in cats, there isn't actually a high incidence of monogamy. So those are some of the data that maybe call into question sort of the primary role of this, like, sort of infanticide, or drive. And I think it's just it's a question up for debate. It's also, you know, it's a phylogenetic question that I think only more and more data really can sort of help us model better. Yeah, yeah,


Nick Jikomes 34:17

is, um, is the extent to which a species is monogamous, also influencing the extent to which they are sexually dimorphic, generally speaking, because I can imagine that if you if you have, let's say, humans, for example, and other primates, a truly helpless, young baby that needs constant care, you really have to have one parent who's at least one parent who's always going to be there. And then because they always need to be there, they might have different sort of attachment styles, different modes of defensive aggression than the other parent might be, have to be more exploratory have to be more risk taking and sort of go out into the world and do different things is is there a relationship there?


Devanand Manoli 34:55

So there is and actually it's, you're bringing up I think, a really cool part which is the behavioral dimorphism but then another interesting thing that, you know, many, many species, whether we're mammals or not, are very sexually dimorphic anatomically right, you know, like, obviously the peacock being one of the best examples, right that you know, and there's all sorts of sexual selection theory that, you know, is sort of models why you see such blatant differentiation in terms of sexual competition. But one of the interesting features both anatomically, as well as behaviorally is that when species have evolved to become monogamous, they actually become less dimorphic, and atomic. And then as you're alluding to, for example, from the context of parental behavior, that includes behavior leads. And so one of the models you might that might come up with is that you're actually looking at sort of de differentiation from sex different standpoint of species as they evolved to become monogamous. And one of the things that actually our work is actually showing is that, that doesn't seem to be the case. Because when you actually start to look at or manipulate the factors that are facilitating monogamy, you actually see sort of the the behaviors almost sort of collapse back to more dimorphic behaviors, so that the brain at least has evolved on top of that sort of original dimorphism, to converge onto behavioral circuits, for example, with parental behavior, that even though paternal behavior and maternal behavior, obviously, in the absence of in with the exception of nursing, look the same, they're actually coming at it from slightly different strategies, at least genetically, and presumably neurally, as well.


Nick Jikomes 36:29

Interesting. And I guess that would fit with what I know to be true for humans, which is that if compared to other great apes, we tend to be more monogamous. And we're actually even though we are sexually dimorphic, anatomically and behaviorally, we are less so than you know, gorillas and chimps and so forth.


Devanand Manoli 36:45

Exactly, exactly. And that's true, even even for rodents, right? And if you look at them in the wild, that it's much more I mean, for us, it's obviously even more difficult to tell sometimes, you know, which is which, but that tends to be the sort of the pattern across phylogeny.


Nick Jikomes 37:00

And so, you know, we're thinking of all these interesting questions, a lot of them have to do with primates and humans, people are naturally interested in humans, because that's what we are. But of course, you can't really experimentally study humans, in very much detail, it's very difficult and time consuming to do this. But there are other species that happen to be the ones that you work on where some of these questions can be tackled in a in a more experimentally rigorous way. So can you talk to us a little bit about the prairie voles, maybe starting with their natural history and what we know about their behavior and some of the similarities between them and us?


Devanand Manoli 37:33

Sure. So. So, you know, from an ecological standpoint, sort of like in the 60s, and, you know, a little bit for them, you know, people were very interested in sort of just patterns of animal behavior and animal survival, right. And the original studies were sort of in the middle of the United States at Southern Illinois, looking at just the behavior of these animals, trapping them, you know, what is their seasonal variation? How does it vary with regards to, you know, rain, resources, things like that. And it was actually studies from little gets, who originally was trapping these animals, you know, when I think he was a postdoc, or grad student at that time, got postdoc, and noticed that, you know, in certain parts of the fields, like for certain areas of these sort of fields in Southern Illinois, instead of trapping, like one animal a time or like a couple of animals, that time, he would often trap two animals at a time, and, you know, then they'd be tagging them. And then if you were likely, so then he noticed that if you were trapping the same animal, you were likely to co trap the other same animal again. And then they started to looking at it look at these pairs. And it turned out that very frequently, with a much higher frequency than other areas or other species, you would see males and females together. And so that led to this original sort of potential hypothesis, that these were animals that for at least whatever purpose were sticking together as male female pairs, which, you know, sort of tends to go along with monogamy. And so that was sort of the original observation that led to this being identified as a monogamous rodent species. And then very soon thereafter, you know, thinking about the sort of now underlying endocrine and neural mechanisms, a researcher named Sue Carter sort of postulated based off of, you know, she's actually interviews even said, in the midst of our expenses, a mother, one of the most profound sort of hormones that we have, we knew was implicated in maternal bonding was this hormone oxytocin. And that's sort of what gave rise to this entire field of thinking about what is the neuro endocrine regulation of what ended up being monogamous mating strategies, but that's sort of where it first came from these original ecological observations long before even we knew that there were hormonal players, let alone what they might be.


Nick Jikomes 39:40

And so the prairie voles, like, how do they differ from just sort of the everyday rats and mice that people might see running around outside? Are they living in big social groups underground? are they sticking together in pairs? What is it little beaver? Yeah,


Devanand Manoli 39:54

yeah. So So, voles are actually an interesting subset of rodents. that, you know, one of the questions is why they may be so convenient for from an evolutionary standpoint that have evolved many, many different glyphs, in terms of monogamy, multiple times across actually multiple geographic regions, both the United States as well as other parts of the world. And so they, you know, as the name suggests, Prairie voles come from the prairies where you have, again, this large distribution with resource scarcity. There are closely related montane voles, there are mountain voles, meadow voles, which are slightly different ecological Paradise, and, you know, they've been named their bank, voles and you know, different types of Geographic Names for some of the species that come from Europe as well. And so one of the features seems to be that they are very, very good at rapidly differentiating, both physiologically and behaviorally into different ecological niches. And so that's been, from an evolutionary standpoint, and incredibly useful set of comparative studies independent, and even when we're thinking about behavior. And as I mentioned, you know, they're basically, you know, the same class of rats and mice, but they tend to, depending upon their sort of social structure, you know, variables tend to have a den with, you know, at least the litter and usually, you have sort of an adolescent generation that often is sometimes dicking, around, sometimes slightly older, they have what's called allo parental care. So they'll actually care for offspring that aren't necessarily their own biologically, there's, you know, they're probably genetic as well as behavioral components based off of who you're living with. That also


Nick Jikomes 41:31

the older, the older sibling, you know, making making something making you lunch when your parents are at work or something.


Devanand Manoli 41:36

Exactly. And so, for variables, that's sort of the context that they live in, you know, other voles species have, you know, sort of mouse like social structures, you know, rats tend to be hyper, hyper social, even though they don't necessarily have pair bonding. And so, you know, depending upon the sort of ecology of where these evolved to live, they have, you know, very social structures.


Nick Jikomes 41:57

So, Prairie voles out in the wild, you know, how does the female meet the male? How do they start to form a pair bond and walk us through what happens, you know, through the courtship phase through the the offspring phase?


Devanand Manoli 42:10

Sure. So, you know, I think there's, there's a little bit of looking for me, right. So, you know, if you're female, females tend to both males and females tend to have some sort of territorial coverage. Males often are the ones that will sort of seek out different territories in particular, if they're wandering away from the nest. And, you know, when they encounter a, a female you know, one other interesting evolutionary correlate that I think, you know, we, we haven't another kind of little bit in depth in the wild is something called incest avoidance. And so monogamous species also tend not to mate with siblings. And I mean, that's a direction we can go in, because, you know, we've done some work to figure out is that genetic? Or is it maybe not. But even in the wild, there tends to be this likelihood of not meeting with a sibling. And so, you know, if both animals are what we call sexually naive sort of virgins, then it's really sort of the initial meeting, that seems to facilitate the both the molecular and the neural mechanisms that cause this pair bond to form. It happens on slightly different timescales, at least when we look at it in the lab, females tend to be able to form a partner preference at least very rapidly, within six hours of encountering a male males tend to take a little bit longer, you know, depending upon the situation of the study, maybe a day or or two. And one of the things that seems to be at least important is sort of the interaction surrounding meeting. And that doesn't necessarily mean like sort of successful meeting and pregnancy. But rather, that sort of meeting attempts that stimulate the induction of hormones associated with meetings or feed for females, it's estrus, these are not cycling animals, they're induced into estrus. And for males, it's presumably some of the hormones that are activated in the context of meeting attempts, potentially being one of them.


Nick Jikomes 43:58

So again, you know, things happen on different timescales. But so this can be quite rapid. And I would presume for the species, a lot of this is mediated through olfaction, they're smelling something, the potential partner and whether it's a hormone or a pheromone or something that that can trigger some of these attachment mechanisms to get started. So


Devanand Manoli 44:15

I think that may play a little bit more of a role in the identification side of things. We know, at least for females, that actually like mating attempts stimulate the induction of some of these hormones, the pheromones are part of this whole equation there there, we know that they definitely play a role in priming the animals to be more sexually active, which probably, like you were saying, activates the circuits, and maybe even maybe, with some specificity, but also, you know, certainly with the level of more general activation for mating, and then as the animals spend more time with each other, investigate each other and pheromones in particulars, right? So most mammals, you know, other than humans, you sort of two different types of smell these olfaction which is what we are used to smelling things in the air, but then there's also pheromones, which are not necessary. really volatile. And so they're the direct interactions with, you know, whether it's tears or whether it's, you know, at the animals bottom, there are pheromones that are specific to these regions that are male and female specific, that also probably mediate, at least in large part, how they identify individuals. And so now we're getting into the sort of the neurobiology of attachment, which is, how do I know that this male or this female is different from basically every other male or female, and that's the one that I'm going to attach to. And some of the work that we're actually doing is suggesting that it may not only be olfaction, or chemo sensation, but there might be other sensory modalities that they're using, and maybe one sex versus the other, to identify who's my main versus who's not


Nick Jikomes 45:41

interesting. So I was at the dog park yesterday, and you know, everybody knows when you get a group of dogs together, they walk around and sniff each others butts. But what they're actually doing there to sort of connect this to what you're saying is, my understanding is that there's actually glands that are secreting pheromones and other things, and they need to get right there. Because as you said, a lot of these things aren't volatile. So they're basically identifying individuals by physically putting their nose against things that their their nose can pick up, right.


Devanand Manoli 46:07

And these, these compounds right are actually aqueous. And they you know, how they're even perceived at a neural level is via sort of an aqueous medium in a different part of, you know, this general chemosensory pathway, just in the same way, like our nose picks up volatiles, these things pick up compounds that are generally in aqueous sort of environments. So I think the dog analogies exactly illustrate illustrate what we're talking about.


Nick Jikomes 46:29

And, you know, you mentioned they're sort of all faction, per se. And then there's this other nose base since sensory apparatus that has to do with pheromones. Everyone has experience with dogs, we know that some species like mice, you know, seem to they use their their sense of smell a lot. And I know that this gets complicated and a little dicey. But in general, people characterize primates as being highly visual, and that maybe we don't use our nose, at least in quite the way that some other species do. My question is really, just before we get into the oxytocin stuff, do humans actually sense? Do humans have pheromones? Do we have that mode of perception?


Devanand Manoli 47:10

So I would say the safest answer, I think, and the answer that I think is pretty much is like the jury's still out. You know, there's, there are a lot of data that suggest that we do sense sort of chemosensory compounds that are related to our biology, the question as to whether or not they're volatile versus non volatile. So you're probably aware of, and they're the studies that are associated with, like, scent of sweat. Right, and that how that modulates attraction. And, you know, that also, at least in some of the early studies, changes with for women's with their, with their cycle, you know, and for men, it varies in terms of like health and things like that, how they, you know, produce some of these these compounds. And so whether that response is actually coming through, what is this sort of accessory olfactory system, or whether it's sort of a modification that humans have, to their primary olfactory system, I think is certainly out, you know, we know that there are these sort of, they're not anecdotal. I mean, these are, these are studies that were done in large numbers of individuals. But I think from a sort of neurobiology system standpoint, the jury's still out in terms of whether we genuinely have what we call pheromones, and most other species, and, you know, other primates, non human primates definitely seem to have are subsets of definitely seem to have preservation of the system, the system that we're talking about. And so I think it's still a question of how much do we rely on those verses? Are they potentially there? And maybe they influence us in ways that, you know, we haven't really teased out for a lot of the reasons that you alluded to in terms of why you can't do these experiments in humans. But in general, Primates tend to be more visual. And I think that potentially is the analogy in terms of how we think about the sensory systems involved in identifying a mate versus, you know, somebody else.


Nick Jikomes 48:54

Okay, so going back to the prairie voles, you know, boy meets girl, they hit it off, and they start mating. And then the female gets pregnant. So after she gets pregnant, how do the behaviors of the male and female start to change?


Devanand Manoli 49:11

So it's actually even before they get pregnant and even independent of pregnancy? And so, there is there's an interesting component that, you know, I think, is a separate set of biology associated with pregnancy. In particular, what happens in the male brain, following you know, either the hormone signals when the female is pregnant, or even after delivery of pups, and there's an interesting, we were, you know, we were talking about infanticide. So there is this, in rodents, at least what's called the infanticide clock, that if a male mates and then there are pups around about three weeks after he's not infanticide towards them, because the likelihood is that those are his pups. And so we know that there are hormone signals that sort of, are communicated or perceived by the male surrounding pregnancy and meeting but for bonding But that doesn't seem to be a requirement. So within those first few days, you know, independent of pregnancy, whatever it is, that happens from a neuro endocrine and neural perspective, between males and females that are induced during these original, or these initial social and meeting interactions, triggers two things. And those are sort of the principal components of what we call sort of, from the social behavior standpoint, pair bonding between the two animals. One is that the animals develop a preference for each other, over now, other animals have the opposite sex. So when you actually test them and give them a choice, they go to their intended or their now, however, we want to call it Patroller. Bonded partner, in contrast to spending time with the stranger animal. The other part of this though, is this flip that I was talking about in terms of the rejection behavior, it's not just that they actually prefer When confronted, for example, with just a novel individual, they actually will actively reject these animals. So it's basically a sort of display. And I don't want to use the term aggression, because I think aggression is different than this sort of rejection. But there's a lot of behavioral overlap when you just sort of look at the behaviors. And one of the questions is, is there neurally overlap between aggression versus this rejection behavior. But you can imagine, from an evolutionary standpoint, you're kind of going against basically 4 billion years of evolution that says, mate, mate, mate, mate, to say, okay, even though you have almost all of the same signals as my partner, I'm actually going to actively reject you. And so those are the sort of two predominant components of what we have what pair bonding really results in and manifests as


Nick Jikomes 51:42

interesting. And then. So then when they have offspring, what what's going on? And what's going on behaviorally, and what's going on underneath the hood, that that is underlying the sort of attachment phase of the parent with the babies.


Devanand Manoli 51:59

So behaviorally, both parents will actually demonstrate really, really robust parental behavior, right? I mean, the one exception that's different is nursing, right? Both animals actually will crouch over the pups in the nest, providing warmth, providing protection, you know, both of them will actually groom them, both of them will kind of attend to them. Both of them respond, for example, when a pup is separated from the nest, to actually retrieve it. And that's a response that is generally guided by the pups vocalizing. And so you really see sort of a significant parallel pattern of parental behavior between the maternal and the paternal behaviors. What's happening under the hood is a really good question. And that's actually one of the questions that we're we're interested in pursuing is, how does you know in the context of this pair bonding, how do we get the demonstration of these behaviors in particular, in males, right, maternal behavior is sort of generally expressed across mammals, you know, varying levels of sort of fidelity in terms of when then how, how robust mothers display these behaviors, but paternal parental behavior is pretty pretty much an exception, unless we're talking about by parental care. And so, you know, as I was talking about whether or not this is coevolution, on to kind of a common final pathway, or in some way, shape, or form, these circuits which may be existed in males, but weren't necessarily active, have now been co opted by these signals by virtue of this bonding circuitry. molecularly and thoroughly, that's an open question.


Nick Jikomes 53:23

I see. So so both parents take care of the young, they do the same types of behaviors, it could be that there's sort of a shared set of neural mechanisms underlying both, or it could be the sort of the male brain and the female brain have done it in different ways. Right. Right. Interesting. So how long does it take for the young to grow up? And what are they, you know, when do things like oxytocin come into the picture? And what exactly are they doing?


Devanand Manoli 53:51

That's a very big question. So, you know, I think the question of when oxytocin comes into play, varies on what what behaviors we're talking about. And so, you know, we know from many, many, many different species that oxytocin is involved in parental and pop sort of attachment, in particular maternal attachment. But, you know, certainly, we would argue that it's probably also playing a very, very, very large role. And pharmacology supports that for eternal attachment as well. And so then, you know, these animals basically are about they grow up for three weeks, at which point at least in the laboratory, we can then basically what we call wean them, so they're then basically self sufficient, they can eat on their own, they can sort of take care of themselves. They are social species. And so this is another interesting question is that if you actually isolate them, from siblings, there are different developmental consequences. And so that the period of adolescence which kind of goes from about, you know, three to, let's say, four or five, or maybe six, seven weeks, depending upon the situation laboratory or you know, sort of the context is a period in which these animals actually form peer attachments that can be even between between members of the Same sex, or interestingly, actually between sort of siblings, whether they're actually genetic or non genetic. So if you raise these animals together, they'll form attachments to each other. And that intersex attachment actually has a potential role for what we were talking about with terms of incest avoidance, that it may not matter whether you're genetically related, but if you're, if you grow up together, you become familiar and attached to each other, but then that sort of leads to you not necessarily wanting to mate with each other.


Nick Jikomes 55:25

I see. So there's probably some kind of fingerprint, whether it's all faction based or something, and it's not necessarily just to do with your genes. And there's, there's something that's in group versus out group distinction, basically.


Devanand Manoli 55:38

So okay, and that's basically sort of the other part of all of this is within group without group and how, how is that communicated? Right. But at least at the first approximation in the lab, it's not genetically dependent, and something that's coming from environmental cues, or sensory cues exchanged between the individuals. And so then after sort of, you know, you have, again, this organization activation, that we're gonna have a hormone sort of kick in, you have sort of the final sexual differentiation of the nervous system and behavior. And then these animals are now reproductively active, right. And so that is where now this sort of phenomenon restarts of bonding between individuals that mate with each other, they do preserve those sorts of peer affiliations from that early adolescent period. So, you know, animals will show up a same sex preference for animals that they're familiar with versus non familiar with. But then, in terms of meeting, that's what sort of results in the pair bonding for the next generation. And the likelihood is actually based off of pharmacology, that things like oxytocin and vasopressin are playing a role at each of these stages, in different ways, and presumably, on different subsets of these neural circuits.


Nick Jikomes 56:49

Can you talk about for people like what is oxytocin? What kind of molecule is it? And how does it work at the cellular level.


Devanand Manoli 56:55

So it's, it's a hormone, but unlike, for example, the steroid hormones that we were talking about, you know, made by the gonads, it's the peptide hormone. So it's a nine peptide hormone, it's very closely related to another nine peptide hormone vasopressin, they both seem to have diverged from a common precursor that's actually conserved, you know, across phylogeny, even like, worms have these precursors. And so these hormones are, they're made from sort of larger peptides. And then they're cut into smaller pieces in different neuro endocrine populations of neurons, within the, in most cases, the hypothalamus, the one that we often talk about is something called the paraventricular. nucleus, it's a principal source in most mammals have both of these hormones as well as other form of peptide hormones as well, even though it's not the only one. And so these hormones are made. And they go in sort of two directions, literally, part of it is into the periphery, which is secreted by the pituitary, and they govern physiology sort of throughout the body, they're involved in parturition, they're involved in various aspects of lactation, things like that. But then when we're talking about this, in the context of pair bonding, they're actually secreted synaptically to regulate the activity of neurons, sort of postsynaptic Li and these hormones bind to what are called G protein coupled receptors, and they're sort of the largest family of receptors sort of in the genome. And by virtue of the binding of these peptides to these to these receptors, there are intracellular processes like molecular events that happen, enzymatic events that change the levels of certain molecules that influence both how a cell or a neuron in this case, can respond to the other signals, as well as that baseline physiology of those cells.


Nick Jikomes 58:41

Interesting, okay. So these things are peptide hormones that are basically small proteins. And part of what they do at least is to basically act, at least in certain cases, like a neurotransmitter,


Devanand Manoli 58:53

right? Exactly. And they fall into this category of neurotransmitter called neuromodulators. And so right, they're often sort of coupled with some of the more direct excitation versus inhibition, neurotransmitters to really sort of influence how the signaling is actually happening at a synaptic level.


Nick Jikomes 59:11

And so I imagine that you guys and others have done experiments, you know, with the prayer balls, you know, probably with other species as well, where you're sort of adding more oxytocin at, you know, some time when it's not supposed to be surging, or you're taking away at a time when it is. So what's what, how does some of these attachment and parental and other behaviors change in response to you know, adding more oxytocin or taking it away and things like this.


Devanand Manoli 59:35

So that was sort of the foundational aspect of the field is, you know, based on those original observations that Sue Carter made about the fact that it seems to play a role people started to manipulate. The other part of this is actually people also started to compare and that's a that's a different direction that I'll talk about in a second. But when they started to manipulate oxytocin, either, like you were saying, giving it in the context of social situations where it might not be yet have been released or wasn't released, but for a shorter period of time, versus blocking it, and, you know, there are drugs that can do both of them. And fairly specific drugs that really, you know, you can give exogenous oxytocin, which predominantly acts adapts to the receptor or a drug that blocks it. It had what, you know, sort of the predicted effects based off of what we think these drugs these molecules are doing, when you gave oxytocin to animals that were put together for a shorter period of time, they developed a partner preference, you know, very quickly relative to animals that got like just a vehicle. Similarly, when you gave either systemically, or then by virtue of those other studies that I was talking about local, either oxytocin to facilitate or blockers to prevent it from working, you basically disrupted the formation of these pair bonds. So if you put animals together, and you've kept on giving them an oxytocin antagonist, you prevent a pair bond formation. And interestingly, similar, similar findings were found in slightly different contexts for vasopressin, this other related hormone that has its own receptor.


Nick Jikomes 1:01:00

And so what happens when you take away oxytocin or the ability of the body to respond to it?


Devanand Manoli 1:01:09

depends who you ask in terms of the animal and the species. And so that was the experiment that we did is if it's okay, I'm going to kind of take a little bit of a side note and talk about the receptor distribution and kind of why that the receptor question is actually a really important one too.


Nick Jikomes 1:01:24

Okay, perfect. So like where the receptor is in the brain?


Devanand Manoli 1:01:27

Exactly. And so because you know, people were really hypothesizing that oxytocin and vasopressin, were playing a really big role in these behaviors, they looked to see okay, are these genes different are the the neurons that make them really different between a monogamous voles species like a pro bowl versus a promiscuous species, let's say metal or montane vole, and when you look at the peptides, they're very subtle differences. But there really aren't major differences. But as you were, as you were speaking to peptides act on receptors. And so by virtue of, you know, the hormones having very large regions where they project to, they then looked at where are the receptors for oxytocin or vasopressin in a monogamous versus promiscuous species. And that's what sort of blew up in the field was that if you look at a monogamous species, and multiple monogamous rodent species, for example, you see that the oxytocin receptor, or the vasopressin receptor, are reproducibly in different parts of the brain, in monogamous species than in promiscuous species. Some of those parts of the brain are ones that you can create pretty good models for, involved their involvement in reinforcing different types of behaviors. So for example, the nucleus accumbens, which is involved in reward reinforcements also involved in sort of aversive reinforcement as well. Expresses lots of Earth has a lot of oxytocin binding in it in a monogamous Yes. So just


Nick Jikomes 1:02:48

just to really simplify that the way I guess, a cartoon way of thinking about that would be so nucleus accumbens, people usually think about dopamine, they think about drug addiction, you know, people get addicted to their kids parents, it's as if you're addicted to your offspring is that you know, how you would start to think about why you might have an oxytocin receptor there.


Devanand Manoli 1:03:06

Sure. And that's exactly how and you know, that's the model that it's, you know, you have to reinforce these behaviors in order to make that facilitate their, you know, them for being beneficial to the animal or for the animal to actually want to engage with them. I shouldn't say I mean, the benefit is the evolutionary side of things. And you know, all of the associated circuits in the parts of the prefrontal cortex, right, how do I, where do I keep the sort of initial or the long term memory of my partner, parts of the other parts of the limbic system that are involved both in meeting aggression as well as just our response to sort of social stimuli? So we've there was this really, really profound difference in terms of where it appeared, oxytocin and vasopressin were acting in a monogamous versus promiscuous species. So that set the stage for all of the studies that really said, Okay, can we start to, for example, initially, because variables weren't mindset didn't have all of the genetic tools? Can we start to pharmacologically manipulate oxytocin or Vasa present in these different sub regions of the brain to really say, Okay, how is it? How are these different regions or different parts of the circuitry contributing to aspects of this pair bonding behavior, and that's sort of what, you know, 30 years plus years of work has really sort of demonstrated that, you know, different regions are contributing in slightly different ways. But that in for, by and large, when you, for example, inhibit oxytocin or vasopressin in some of these regions, you really significantly impair the animals ability to pair bond. And so that led to the experiments that we have recently, recently, we've been working on this for quite some time that we did was, which was to bring molecular genetics to the variable. And part of that is kind of motivated by my own sort of way of thinking about innate behavior. And that's I come from this might be the genetic perspective, thinking about using the genetics of a species to really identify the neurons that are involved in innate social behaviors, right? And so, again, because receptor is in these different places, it points you to the different parts of the brain that might be involved in social attachment. But variables weren't mice, you know, they didn't have the decades of molecular genetics and cellular biology and embryo embryology that sort of has allowed us to really develop tons and tons of tools in mice and other clinical model organisms. You know, they were a species that really was, you know, they were had a rich behavioral history, which pharmacologic history, but we didn't have the ability to genetically manipulate them. So we developed those tools using CRISPR, cast nine, eventually, and there was a precursor to that have been impressive five or six years that we can't or don't need to go into. But we used CRISPR technology to, in this case, knock out the oxytocin receptor, for two reasons. One was just as a proof of principle that we could genetically manipulate things in approval, and then really start to do sort of the next level of molecular genetics and neurobiology in the species to really get at the circuits and genes involved in pair bonding. And then also, you know, to sort of just ask the question, which we expected a very specific answer, that, you know, what is the genetic requirement for oxytocin receptor signaling for pair bonding, but the idea being that it would have a pretty significant impact on the ability of these animals to inform.


Nick Jikomes 1:06:17

I see. So before we get to the result there, yeah. So the expectation I think people would have is, we know oxytocin is important from these things, we know that the distribution of receptors in different parts of the brain is different between monogamous animals and non monogamous animals. Obviously, you would imagine that if you get rid of the oxytocin receptors, something major is going to happen before you describe that results. So use CRISPR to get rid of this receptor in Prairie voles. Did you? Did you just knock it out completely everywhere? Or did you do it for certain brain regions, or both?


Devanand Manoli 1:06:48

So the first experiment we did was to knock it out everywhere. And so we made what's what's called a knockout animal. And that that, again, from the proof of principle standpoint, is the sort of the principle technology that allows us to develop all of these tools in mice from a transgenic perspective, right. So you can use things like viruses to manipulate genes in certain ways. But at the end of the day, you need to make different forms of different genes, different alleles, right, either to conditionally manipulate them, like you were saying, in different parts of the brain, or, you know, to build tools to label neurons by virtue of the genes that they express. And that's sort of what's led to the revolution in molecular and circuit neuroscience in mice is because we can define circuits based off of the genes that they express different populations of neurons, based off of the genes that cross and then manipulate them using the sort of intersection of these two types of technologies. And so what we did was to really spend a lot of time being able to bring CRISPR, into the ball embryo. And that involves just a lot of time understanding how full embryos develop, what's the biology, you know, at the other end of the animal instead of the brain that really allows you to manipulate them at a genomic or, you know, sort of genetic level.


Nick Jikomes 1:07:57

So eventually, you guys figure it out, you get the technology to work, you knock out the oxytocin receptor, what happens?


Devanand Manoli 1:08:04

So we were surprised that not as much happened as we initially expected. So you know, we, I often talked about now that my postdoc, you know, who was doing a lot of the studies, we made the animals initially, there weren't any obvious phenotypes, like they didn't have severe growth deficits or anything like that, which, you know, I don't know, that you'd necessarily expect with loss of oxytocin receptor, but then we click Sort of what we'd say cleaned them up genetically, and then started to look at their behavior. And we're actually quite surprised that when we looked at the behavior of animals that had been put together for a significant period of time, they showed very, very robust partner preference. And then in collaboration with sort of, actually, the lab that I met, the mentor that I did my postdoc with, and our collaborator, is in Russia and Karen bales, we, you know, we looked at multiple alleles, and we started to look at different aspects of their pair bonding and parental behavior, and found that they do develop very, very robust partner preference, and demonstrate very robust parental behavior, which, you know, I think, based off of the pharmacology, I would say, was a little bit of a surprise, because there was really this sort of idea that, you know, from the perspective of disrupting oxytocin signaling or facilitating it acutely, you really had profound changes in the ability of these animals or the propensity of these animals to form pair bonds. But then at a genetic level, clearly, that wasn't the case. You know, I will say that we are looking at other aspects of the behavior. And perhaps not surprisingly, as a sort of a neuro geneticists, we see that the genetic architecture of pair bonding behavior actually is, you know, it's multifaceted, right? And so whereas this initial disruption wasn't something that's prominent, there are discrete modules that do seem to be dependent upon oxytocin receptor signaling, what isn't the case is the ability to form a preference for your partner.


Nick Jikomes 1:09:55

Okay, so a lot of these behaviors are intact, even in an oxytocin if you get rid of The oxytocin receptor everywhere using this CRISPR technology. But you just said that there were there were some things that were disrupted, disrupted, what were those.


Devanand Manoli 1:10:07

So how they so the sort of two areas where we're really focusing is on the reciprocal behaviors between these animals. Right? So how do animals actually interact initially, between each other? Eventually, they clearly can form a partner preference. But are there actually subtle differences in sort of the social interactions that they engage in? If one of the animals is lacking oxytocin receptor? And the other one isn't? Like you? Can they detected? Do they behave differently? With one versus the other? How is that happening? And so there is definitely this sort of overall effect in terms of probably the patterns of social interactions that facilitate pair bonding, are altered, even though the animals eventually can form this partner preference.


Nick Jikomes 1:10:46

And so So yeah, it's a surprising results, sort of the naive expectation, I think most people would have had is, okay, if we get rid the oxytocin receptor, we're sort of gonna break all of these behaviors that we've been talking about. But you generally don't see that. And where my mind goes with this, I started my training in evolutionary developmental biology. And, you know, one of the sort of core things that that I learned from that era of my life was the relationship between redundancy and robustness and development. So a lot of times, you know, you'll have multiple copies of a gene or protein or something. And these things are highly overlapping in terms of what they're doing and where they are. And the basic idea is, you know, development is complicated, it needs to go right. And there's lots of ways and places it can break. But if you've got multiple redundant versions of things, if one of them breaks, you've got a backup, basically. And so you mentioned earlier that there's this other thing called vasopressin, it's also this sort of peptide that's very similar. Do you think something maybe is going on here where you've got redundant peptides that can compensate when one is gone.


Devanand Manoli 1:11:47

So there's, there's sort of two questions there. And one is sort of the redundancy from the peptide perspective, but then this is actually also talking about the receptor. So then we've sort of been making the argument that the vasopressin receptor may now be sort of playing the role for where receptor was, we didn't see that when we looked for sort of significant changes in the vasopressin receptor expression in the oxytocin receptor mutants, we didn't see that there may be in very, very specific sub regions, a place where vasopressin upregulation, or receptor up regulation is, or even where it is, generally, is somehow responding to oxytocin. But at a global level, that's not where we're seeing the redundancy. I think, what probably, you know, apropos of your, your point, from an evolutionary perspective is, you know, these are behaviors that are absolutely critical to the species, right. And so there is a fundamental difference between disrupting a neuromodulator in an otherwise wild type animal that's developed with all of the neural and developmental homeostasis, that allows it to be a functioning wild type animal. And then you come in and you dramatically alter the function of the circuits, versus as you were suggesting, when you don't have the gene itself in the get go, there are redundant or compensatory mechanisms. And, you know, that's an open question is, one of one of the things we're looking at is what are the changes in gene expression that have been plus or minus the oxytocin receptor, that compensate for the absence of oxytocin receptor signaling. And, you know, again, I say that we were surprised. But you know, I think if we take a step back from so again, from an evolutionary perspective, you're not going to have a single point of failure, right, these animals have to have robust systems or evolution would suggest that they need robust systems to really make sure that they can maintain themselves and propagate, right. And so it's not going to be that suddenly, if a single signaling pathways slightly disrupted or in this case globally disrupted, that they can't still facilitate their reproduction.


Nick Jikomes 1:13:43

I assume that this is the direction things will go as the technology develops and gets more and more precise, but just in sort of molecular developmental genetics, broadly speaking, you often see differences in experiments where, you know, you do a whole gene knockout right from the beginning. And that sort of gives space for so to speak to the body to come up with as much compensation as possible. versus, you know, you start to develop ways to knock out the gene in one place that like a very well defined window of development. Do you think that's where things are gonna go? And that you'll probably sort of unmask some more significant phenotypes when you do those more caught up? Especially with samples?


Devanand Manoli 1:14:19

Yes. So I think the short answer is yes. And that's certainly the direction that we would like to go and is to be able to manipulate the neuron there, the receptor expression, you know, after an animal has had the chance to develop and see what are the effects, you know, sort of with local district, or even developmental? I mean, you could do it both ways. Right. And, you know, to your point about the more sort of both subtle phenotypes, but also more profound effects is, you know, there are other aspects like I mentioned this, you know, the flip in rejection behavior, right, that seemed to have more of the oxytocin receptors, and it seems to have more of a role there. And so I think both in terms of what the global Knockout is really showing us is that there is this sort of circuit slash genetic separation in terms of how these aspects of have attachment behavior or being regulated. But I think the, you know, the question of what happens when we just take it out in the context of an adult animal is a really, really important one. And also is, you know, these are all orthogonal in terms of really understanding what are these circuits doing? What are they responding to, and then, you know, both at a sort of global circuit level, but also at a synaptic level, what is oxytocin receptor signaling doing in different subsets because even though the receptor is the same, there's only one receptor in the genome, it's going to have different effects, depending upon the cell type that it's in, whether it you know, I mean, both molecularly within the cell, but also, it's the same receptor is doing the same thing, but it's gonna have different consequences, but also different cell types. Like if you have it in an inhibitory neuron, versus an excitatory neuron versus a certain ergic neuron, you can imagine, all of these things will have very, very different readouts for behavior.


Nick Jikomes 1:15:52

So going back to behavior and the natural ecology, the prairie voles and trying to tie a couple of things together. So we talked about earlier how sort of one theoretical reason to explain like why monogamy evolves in certain lineages has to do with resource scarcity, basically. And we've talked a little bit about, you know, we've talked about pair bonding in groupers, out group distinction, incest, avoidance, things like that. So like with all of that stuff in mind, I can imagine that, okay, you've got a pair of prairie voles, they've got to litter, the litter, they raise the litter, and, you know, it becomes time for the kids to venture off into the world on their own. And on the one hand, you know, you want to take care of your offspring, they're your offspring, of course. On the other hand, if you're a prairie vole, and you've specifically evolved this reproductive strategy, because of resource scarcity, you know, at some point, you've got too many mouths to feed, and maybe you need to kick kick the little ones out of the nest. In fact, I used to have that parakeets. And one of the behaviors I observed when, when I enabled them to have an estimate is, you know, the mother would they would both the respite parental care, the mother would stay in the nest the whole time. But at some point, the babies got big enough and louder enough and hungry enough that she just said she basically became aggressive, and she would attack them until they left, do you see that type of thing with variables do they sort of actively make their young go away.


Devanand Manoli 1:17:18

So in the wild, there definitely seems to be something that facilitates the sort of the older, young from leaving the nest. There hasn't been very, very reproducible documentation of aggression, per se. And it may actually coincide with the young leaving when there's larger resource availability to then go find their own territory. But what to what you're talking about that is actually something that's seen, for example, in in candidate species is that you actually have, at some point in time, that you have reproductive suppression by the mating pair, so that the actually the subordinates don't mate until, like you said, the neck gets too big. And then they actually they're ones that are, kind of have a higher likelihood of meeting that then they force out for exactly that purpose that also allows those animals to then go start their own sort of nest and clan. And so with payables in the in the laboratory, we don't really encounter that to the certain extent, because a there's not a huge resource scarcity, and we don't try to use that as a manipulation. But we also remove the, you know, the young from the nest, at some point in time, unless we're specifically looking for this Allah parental care in the wild, you know, I would not be surprised if there is some level of sort of behavioral modulation of how they sort of deal with that in the context of either too many pups in the nest or when resources become scarce. But it's not something that we would be actively see. And in part, that's also because they develop, they demonstrate such robust Allah parental care, right. So in many cases, you actually see that they're taking care of the family, even though they're not necessarily reproductively active.


Nick Jikomes 1:18:51

I see. And, you know, one of the things that characterizes a lot of species is, you know, when when the mother has offspring, she obviously becomes very attached to the offspring and cares for them. But simultaneously, mothers will often become hyper aggressive or defensive, at least towards intruders, right. They don't want. You know, the classic example is like, My family's from Michigan. And my parents live in northern Michigan. So everyone knows about bears up there. And basically, what everyone understands is, you know, black bears are mostly not a threat, most of the time, they're not going to bother you, they'll typically avoid you unless they're starving. The major exception being if the mother is with her cubs, in which case, you just need to get the hell out of there. Right, right. So the elephant example that you brought, yeah, yeah. So thinking about oxytocin. So with that in mind, you know, oxytocin, the sort of cartoon version that you see, you know, magazines and stuff is, it's the love hormone. It's a cuddle hormone. It's just sort of the signal that makes you love whoever's around you. But I also know that there's some work out there and I'm not super familiar with the details, that it might have a role to play specifically in the sort of in group out group distinction thing where it's sort of If you're in the group, you're going to be more altruistic and, and display care behaviors and things like this. But if you're in the out group, people or animals might be more aggressive or more selective and things like this. Is that true? And what do we know there?


Devanand Manoli 1:20:14

So that's certainly true. And, you know, I think the example is, you know, I think the closest example is to maternal aggression, right. And the, the fact that, for example, the mother will defend against any intruder, except for her partner, right, in terms of the or I shouldn't say, any intruder, that isn't some somebody that she is familiar with, right? So others offspring that are part of the plan, are not somebody that she'll fight against, but a mother will very, very actively defend against any potential intruder, male or female, into the territory. And the same thing seems to be true. You know, I would say, with some of the studies that have been done in humans, in terms of in group out group, you know, there have been some studies looking at, for example, people who are in relationships, who, you know, if given oxytocin actually show a stronger aversion to an attractive member of the opposite sex, because it facilitates what you're saying is this sort of othering. And I don't, that's a term that has a lot of weight in different contexts, you know, both in sort of the psychology literature, the sociology, literature, so I want to be very careful about using that. But I think that what we're seeing is exactly what you're talking about is that you're amplifying the response to familiarity from different contexts, whether it's your offspring, whether it's your mate, your siblings, as a consequence of that, you're also filtering with a higher signal to noise ratio, anything that's not familiar, right? So anything that is the other, which then beat, which becomes very important for, for example, your response to a novel me, right? How to identify my mate versus another mate, they're gonna be subtly different. You know, for us, we think everybody's face is so unique, I think they are, but probably to evolve, it's, you know, a primate that looks basically the same. Similarly, you know, for us, they're going to be subtle differences between the bulls pheromonal profile, but those need to be amplified for an animal to identify, obviously, with other behavioral contexts and cues. This is my mate versus this is not my main. And if it's not my main, then I actually evoke a very, very different behavioral response, which is this projection behavior. So I think that that that is exactly the neurobiology that operates at multiple levels, depending on how complex the social group is.


Nick Jikomes 1:22:21

So okay, so they've done experiments in humans, where you basically give exogenous oxytocin. And people become more averse, or at least less attracted to attractive members of the opposite sex.


Devanand Manoli 1:22:32

Yeah, yeah. And I will say, There's one caveat that, you know, sort of the intranasal oxytocin is still its own sort of debate in terms of how much of it actually gets there. But it did have an effect. So I don't want to speak to whether or not I, you know, the biology of what happens when you give intranasal oxytocin. But that has been an observation in humans. Yeah.


Nick Jikomes 1:22:51

Interesting. Interesting. Wow. So what


Devanand Manoli 1:22:57

you just reminded me of another thing, the other place where people have sort of looked at oxytocin is, for example, in like, people who are really, really into certain sports teams, right. And so far as you can actually monitor in that context, and the your, your team scores a goal, people, people's oxytocin levels actually do go up. And I mean, that's been something that's reproduced, obviously, in sort of smaller clinical situations, but seems to be the case, and also makes you you know, the higher the level of oxytocin you have, the more likely you are to then demonstrate some sort of aversion towards the other team. Right. And so this idea that it's it's amplifying responses of who I'm with versus who I might not be with is pretty consistent.


Nick Jikomes 1:23:37

I see. Yeah. I'll let everyone ponder their own examples from their own life of sports and in group versus out group. But that's, that's it's a really fun area to think about. I want to ask you about so we'll, I guess we'll stick with the parables unless we should go somewhere else for this. But you know, what happens when you disrupt one way or another? Some of these parent offspring interactions, and the offspring are not getting the kind of parental care that they're supposed to be getting in a normal ecological circumstance? What happens? What does that do to the subsequent sort of social and sexual behavior of the offspring when there's some kind of deficit in parental care?


Devanand Manoli 1:24:17

So So I think you already alluded to that this is something you can start with independent variables, right. So there's been great studies from Michael meany beginning that was actually looking at innate differences in how rat moms sort of took care of their pups, and showed that pups who were the offspring of high grooming versus low grooming being sort of like the sort of extreme measures of those initial groups actually had reproducible patterns of parental behavior themselves, in particular for females. And so that, you know, female pups from high grooming mothers grew up to be sort of from the rat literature, good parents. They showed very, very attentive parental behavior, good pup retrieval and a lot of group In behavior, versus female parents who are female pups who were from low grooming moms grew up to be low groomers. And also, you know, sort of that persistent, they also had other parental behaviors that showed a deficit. And so there's certainly a reproducibility and sort of a transmission of these behavioral consequences by virtue of these early life experiences. Similarly, in the context of both parental behavior, and now kind of moving into variables, parental deprivation has pretty significant effects and reproducible effects on late life patterns, both of just general social behaviors, as well as pair bonding and parental behaviors. You know, one of the things that we're also very interested in is, you know, parental deprivation is incredibly severe, right. And we know from clinical populations, even in the absence of sort of the nutritional deprivation, that can also be, you know, a consequence of isolation. But if you take that away, for example, the Romanian orphanages studies, right, which, where you had individuals, where they had all of the nutrition provided, but didn't have the socialization. In some cases, when you're talking about the kids that were there, from the earliest stages of life, they developed what those clinicians called called pseudo autism, a very, very, very profound set of disruptions in their social cognition and social behavior. But in addition to sort of other clinical sequelae. The same thing is also true in animal models, when you talk about this parental deprivation, it's a very profound effect. So then the question is, can we start to separate out the stages of social deprivation, and also, the specific effects of social isolation, social deprivation, from other types of stress, right, thermally, things like that. And so that's actually something that, you know, we and others are starting to look at in variables and are finding that there are these very reproducible effects that if animals are sort of socially isolated, even later stages of their life, but you know, prior to adulthood, it does affect their propensity to form pair bonds, it also affects their propensity to, again, have this rejection behavior. So sometimes coming back hyper social, and, you know, will form a preference if given a choice, but then also, if, you know, just confronted with a new individual, they're totally willing to meet with that individual. And there's also interesting differences between the sexes, for how these things play out.


Nick Jikomes 1:27:14

Can you go into a little bit more detail there? And maybe talk about an example? Sure.


Devanand Manoli 1:27:18

So, you know, for example, if we take animals that, like, so, animals that are socially deprived, early, early in, in adulthood, not necessarily complete parental deprivation, but you know, periods of social isolation


Nick Jikomes 1:27:30

exist? Do you just mean the sort of, you're not allowing the parents to be there for some fraction of the time,


Devanand Manoli 1:27:36

right? So you can you can do that, like sort of individual periods of isolation, or sometimes what people have done his very, very rigorously tried to say, Okay, we're going to give them warmth, we're going to give them nutrition, but we're going to take away the social context, right, the actual parent, which, again, you know, they're how you measure the severity of the stress? I think it's, you know, that's a tough question. And if you look at what happens to those animals, you know, in some cases, what you see is that, for example, the females will form a pair bond, you know, if again, given a choice, even though it's pretty, you know, the, the strength of that pair bond may be, depending on the metrics, less severe. But then if you give them a male, a novel, male without their partner, they actually treat that as they would a novel animal like not having been bounded.


Nick Jikomes 1:28:22

So they don't, they don't reject Him.


Devanand Manoli 1:28:24

Exactly, exactly. And in some contexts, the use is almost the opposite in males, that they sometimes become very highly social, or actually, you know, depending upon the model, or how you're testing it, they may be more anxious. So they're not more pro social, even in terms of the initial social interactions that lead to pair bonding. So they take longer, they have less sort of robust pair bond. And then, depending upon the context and the level of stress, sometimes you see the similar phenotype to females where they become hyper social, sometimes you actually see that they're even more rejecting that. So they have sort of this hyper attached, even though it's less social phenotype.


Nick Jikomes 1:29:03

I see. So, so poorer. So in general, it seems to be a whether you're male or female, and exact pattern will differ between the sexes. Not having the parent there as much being deprived of parental interaction seems to push them to one end or the other of the distribution of normal Perryville social behavior.


Devanand Manoli 1:29:21

Right, right. And that's consistent with the studies in rats, where, you know, when you had the females that were sort of raised by the sort of the low grooming moms, they not only were not necessarily the best mums, but they were also they had much more frequent meeting. So they would have bend in their pups at an earlier time point in order to mate, and then mate and mate and mate.


Nick Jikomes 1:29:40

Interesting. There's a couple directions we could go with that. I mean, one one is a little bit more theoretical. I know that there's some ideas out there on basically you take the concept, which a lot of people learn about in grade school of art versus case selection. So like, you know, so you have some species like humans, for those listening where we're We're sort of one extreme example where, you know, we put a lot of time and effort into our offspring, you know, so you have to really be, you know, babies are helpless, you have to be there and invest years and years and years of resource allocation and attention and care to them. Whereas you think about something like a salmon swimming in a river, there's none whatsoever, right? The females just lay eggs, and the males just sort of, you know, put their sperm in the water, and they try to have as many babies as possible now, knowing that there's going to be no investment, and most of them will die. This, can we think about some of these behaviors within a single mammalian species like this, where one one of some of these things that you're describing that we think of as deficits or something, could also be thought of as different types of strategies for different types of environments with different levels of investment.


Devanand Manoli 1:30:44

And I think that's a really, really important point to make. Because, you know, especially when we start to analogize, some of these behaviors, humans, you know, these things have evolved for many, many different selective pressures, right. And so the context in which what we call sort of a deficit and behavior may actually in there's sort of these evolutionary theories of various neuropsychiatric conditions, and why certain things manifest in different contexts, which, you know, that's its own conversation, but I think that what you're getting at is that, you know, the plasticity of the circuitry is, is there, right. And in different contexts, you're going to have a different adaptive strategy for survival, right, within a species. So there's, there's kind of the the interest species versus the inter species comparison that you're making, right? So we know that promiscuous species tend to have larger litters, right, because of sort of that phenomenon that you're alluding to that, you know, it may be to their benefit, just put as many offspring out there as they can hope that they survive, and, you know, good, versus a species where you have by parental care, and you're investing inordinate amounts of resources into the offspring that you have, they actually have fewer offspring as a consequence of that. But in the context of either environmental or sort of social stresses, it may actually be very adaptive, you know, for whatever reason, if you know, there's a couple more hawks in the area, and your parents are, you know, getting picked off, you know, left and right, it may actually make more sense to sort of adopt a very different mating strategy in order to propagate your your genome.


Nick Jikomes 1:32:08

Yeah. And, you know, your work is really interesting, because you're, you're studying these prairie voles is very interesting rodent species and doing this basic research. But you're also a psychiatrist. And you know, on the one hand, you don't want to anthropomorphize too much when you're talking about rodents, you don't want to over generalize the findings from from one species in one slice of the experimental field that you're in. On the other hand, you know, there are some really interesting parallels between the prairie voles and the humans. And it's really hard not to think about how some of this applies to many, many human circumstances that probably come up as people are listening to what you're talking about. How do you start to use your basic research findings to think about human neuro neuro psychiatric conditions and social deficits and things like that?


Devanand Manoli 1:32:57

So there's, there's a couple of ways that I think about it. You know, one is certainly actually the you know, the very basic question is, what's the point of studying these behaviors, even though we can sort of, you know, anthropomorphize or make analogies at a behavioral level? Is that really biologically useful, right? And that kind of goes to the point that, you know, I mentioned that when we look at sort of monogamous route and species you see sort of convergence on oxytocin vasopressin, but that seems to be across sort of phylogeny, that when species have evolved, or just even sort of diverged, different social strategies, these peptides come up more often, if not, every time. And so and then when we start to look at mammals, whether or not it's more oxytocin, more vasopressin or more, you know, maybe even a different hormone, you see these conservations have kind of converging on brain regions converging on molecular pathway, neuromodulatory pathways. So there's at least that prima facia sort of analogy that says, Okay, there's some utility in terms of understanding the biology of how we are as a social species as a social species, by in an animal model where we can really understand their social biology, then there's also the sort of the genetic and the sort of circuit aspect of it. And, you know, as we're sort of exploring more and more, we see that there are similar patterns of genetic sensitivity to in variables, using the technology that we have to some of the sort of well established genetic contributions to different neuropsychiatric disorders in humans. And so, again, from biologic biological standpoint, there is the ability to say okay, at least we're looking at something that maybe a really, really significant distillation of how complex social behaviors in humans, but there's some patterns that are emerging in terms of what's happening. And that's where I think the importance of any work and the basic science model is for psychiatry is, you know, it allows us to generate hypothesis not only about what's happening, but how do we treat, you know, a given set of conditions, right, whether it's, you're talking about, you know, the sort of social aspects of depression or anxiety, my interest, as I mentioned in early psychosis, And one of the things that we are very, very lacking in terms of treatment in that population is what we call negative symptoms, the social cognition and social components that are impaired in different populations. And so really trying to think about how can we even think about the biology, let alone a treatment for some of these neuropsychiatric conditions. That's where I think a lot of the utility of understanding the basic sciences and you know, historically, psychiatry has, like many other fields of medicine initially, that it's been a lot of trials in different patients to see what worked. But more recently, you know, we now have some of the first drugs that are based off of hypothesis driven basic science, actually, what you know, the first one was actually a hormone based drug for postpartum depression that was based off of what was known about the biology of park tuition, what happened, you know, in for women and mothers immediately postpartum? And how does that potentially correlate with what's seen in patients with postpartum depression, which led to the development of a drug specifically for that? So I think that's how sort of the general aspects of thinking about this from a neuro psychiatric standpoint, come into play.


Nick Jikomes 1:36:06

And that drug for postpartum depression? What is it exactly? And how does it work?


Devanand Manoli 1:36:10

It's brexanolone, which is it's a, you know, it's a steroid hormone analogue, that is one of the metabolites that changes very dramatically postpartum. And different populations of women postpartum, had different drops, basically. And it was noticed that the the most significant drop in brexanolone, it's the hormone analog, correlated for women who had postpartum depression. And so then this analog was developed, specifically in this context, and actually, you know, has gone through FDA approval, and that was actually sort of one of the major treatments for that,


Nick Jikomes 1:36:44

how well does it work?


Devanand Manoli 1:36:47

I mean, very well, I mean, you know, no psychiatric medication works, as well as some of the other ones. But it actually, you know, it's well above placebo, and it actually, in specific populations of women with postpartum depression is incredibly effective. Right. And it's, it's one aspect of the Muriatic biology in this very, very specific context for for women, so but I think that's actually sort of alluding to why I think the basic science is so important, you know, I mean, as humans, we are very diverse, biologically, and genetically. And so, you know, the problem in psychiatry is that it's very hard to identify a patient population that shares the same biology, even though they may share the same symptoms. And symptoms are just external, not arbitrary. And I don't in any way want to sort of minimize the importance of really understanding how symptoms present. But the the pathways that lead to some how symptoms present, are very diverse. And so being able to then say, okay, if I take a population that has sort of behaviorally the same sets of symptoms, can I start to understand what the underlying biology is and how it may be different, you know, between different populations to say, a treatment that works in this, this group of patients may not actually work? And I don't want to have to just try it. I want to be able to say, can I identify who may respond better versus whom who might not?


Nick Jikomes 1:38:04

Yeah, so in the time remaining, I want to talk a little bit more about your clinical practice. So I think you mentioned that you study childhood psychosis.


Devanand Manoli 1:38:13

And I'm not I'm not a clinical researcher. But my, yeah, the clinic that I'm in is basically, we work with kids, sort of across the spectrum of various conditions that are starting to show are starting to report, what fall into this category of psychotic symptoms. What,


Nick Jikomes 1:38:30

what is psychosis, that term can trip people up sometimes. So let's talk about what that means. So


Devanand Manoli 1:38:35

when we use the term psychosis, and I apologize, I'm going to start to sound a little bit like like, like I sound in the clinic, it's a very broad term that has no one specific cause. And so when we use the term psychosis, it can include things like hallucinations, auditory, visual, actually, olfactory hallucinations are the most common. It can include things like paranoid thoughts, it can include things like delusions, it can include disruptions to cognition, so what we call it sort of just disorganized thinking, also slowing of cognition, blocking of cognition. So these are now some of the things that are in this negative symptom component. It also includes, in the context of some of these illnesses, disruptions to social cognition, either being able to perceive social signals, express them, or sort of integrate them into a social context, right. And the important fact is that you don't have to have all of these, you can have various combinations of them, that sort of generally fall into this category of what are sort of psychotic, psychotic or psychotic like symptoms. And then the other part of it is importantly, there's no single cops rate. You know, many, many kids actually report these symptoms, and there's not it's part of just natural stages of development. Obviously, as many of us are familiar with people can have this nation of things because of drugs and you know, the pharmacologic things because of fevers. You can have many of these symptoms, and also because of various psychiatric conditions like depression, like schizophrenia have, you know, like bipolar disorder. So all of these can actually sort of manifest in different contexts with this general set of symptoms that we call psychosis.


Nick Jikomes 1:40:09

And so I guess the real problem is when some of these things are actually showing up in an at an inappropriate time or in an inappropriate way, in a way that's not typical. And or they persist longer than they might just sort of sporadically pop up for the average kid is that more or less accurate.


Devanand Manoli 1:40:28

And the one thing I would also add is when they're disruptive, right, because it's possible that some of these symptoms can actually occur. And they're not disruptive because people have either learned to cope, or they're just not, you know, intrusive, in a way that actually disrupts their ability to function. Right. And so if that's the latter category, obviously, from the perspective of a clinician, that really brings somebody to our clinic, right to say that this is really interfering with, you know, my child's life or my life. And now we have to figure out how to how to help them.


Nick Jikomes 1:40:55

Are there any, you know, obviously, there's a lot of diversity to this, as you said, both and how this stuff shows up, and and what's driving it. But when you talk about childhood psychosis, broadly speaking, are there any forms of this that are more that you see more common, commonly? Or are there any things that are becoming more common in recent years? And if so, what are they?


Devanand Manoli 1:41:18

So I would say that, you know, sort of in terms of the patients that we see, there is not a single common thing that really sort of unifies even a majority of patients. You know, I will say that there's certain neurodevelopmental syndromes that have a higher likelihood of presenting with psychotic symptoms. So I think, you know, probably the example that's most commonly understood is autism spectrum disorder, right. And autism by itself is an incredibly large spectrum. But we do know is that where you have children with a diagnosis of autism, there is both genetically and sort of, you know, epidemiologic, a higher risk for the development of psychotic symptoms. So that one context in which we see sort of a sensitization and, you know, for the, for the children that do develop them, they tend to develop them a little bit earlier than kids without a diagnosis of autism. You know, and they also share very similar patterns, you know, sort of independent of that. So I think that might be one where you could sort of say, Okay, there's, there's a potential sense of sensitivity, or sensitization, you know, because of the factors that contribute there. But, you know, I mean, these symptoms can be reported across the spectrum in terms of early life trauma can can lead to this, that by itself is a risk factor for the development of what we call these formal psychotic illnesses like schizophrenia, it contribute, and there's a whole interaction, like we talked about, about development and stress and the vulnerabilities of the brain that, again, bring it brings a lot of biology and a lot of sort of human experience, to the question of what what is causative? Then there's one other thing that I was gonna say that I've now kind of forgotten, in terms of Oh, and then in the context of just very complex medical illnesses, right, you know, when anyone is very sick, you know, you may have had the experience of somebody who's in the hospital, who have psychotic experiences, you know, like, consistently delirium, because they're just very ill, the same thing can happen when a child is just very sick, you know, either because of a condition or just happens to be very ill for various different reasons, they can develop, because their brains are developing potential sensitivity to some of these symptoms,


Nick Jikomes 1:43:21

do psychotic, like symptoms, do they happen more frequently at certain, like developmental transitions or phases? So like, for example, you know, when you talk about, like, the onset of puberty for you know, colloquially, we say, oh, teenagers, their hormones are raging. And we talked about it that way. But your hormonal patterns really are changing. And, you know, we've all had the experience growing up of, you know, going through some of these transitions, and you know, different aspects of your psychology and your behavior are changing, do you see sort of transient increases in things like psychotic, like symptoms at certain periods of childhood or adolescent development?


Devanand Manoli 1:43:57

So I'm gonna separate that question in terms of when we're talking about a clinical population versus not. So prior to puberty, you know, in during childhood, children will vary like 70% plus of children will report some sort of like, I'd like to hear something or I saw something, right. Whether it's part of fantasy play, whether it's, you know, just part of the biology of the developing brain, it's within the realm of normal child development. And you know, there's no, for the kids that do versus the kids that don't, there's no late life early in later life sequelae. But to the point that you're talking about what we do know is for, for example, what we call these formal psychotic illnesses like schizophrenia, there is a very significant role for adolescent development and assume gonadal hormones because there's a difference between how males and females develop. The other correlate in terms of the gonadal hormones in particular, is there the second peak for women around menopause, in terms of the development of some of the psychotic symptoms or psychotic illnesses? So the trajectory that we find is that, you know, kids, often, and this is actually one of my interests in terms of understanding the the social biology is to identify, are there predictive factors prior to the onset of some of these more more common sort of presentations that we associate with, for example, schizophrenia, like hallucinations, or delusions and paranoia that happen once adolescent starts. And it tends to be that for males, they're a little bit more sensitive earlier. Versus for females, they tend to be a little bit offset a little bit later. And so, you know, when you're teaching this, to sort of medical students alike, sort of the way that you sort of think about it is for males, you often see the the sort of peak in these symptoms, even though it's preceded by a couple of years is right around high school graduation is around 18. So 16 to 18, is where you sort of start to see the big peak happening for males, and for females, maybe around college graduation, so offset by four years. And but then, as a consequence of that, and there's a lot of active work trying to understand, is it because it's happening earlier for males, that they tend to have more severe symptoms? Or is it that there's actually differences in terms of how the gonadal hormones are working in one context versus the other that causes different severity. I mean, you can imagine, the more time a brain has had to develop, in the absence of some of these stresses, the better off it is, and more resilient. It is that one explanatory model, we also know that there seems to be an effect of, you know, it's a female protective effect of potentially estrogen and other hormones that may then explain why menopause is the second sort of peak for women in terms of the onset or presentation of some of these symptoms.


Nick Jikomes 1:46:44

One last question before we wrap up, because it just occurred to me to kind of connects a couple of things that we that we've talked about this whole time. So you're just talking about menopause, this sort of phase later in life that that females have. And we talked earlier about prairie voles and monogamous species and species that have intergenerational cohabitation and allo parental behavior. So Mike, with all those things in mind, my question is, what what is the point of menopause? Why would you Why Why would a species even evolved something like


Devanand Manoli 1:47:15

that? So that I think that's an excellent question. And I, you know, there are many, many evolutionary theories about the point of menopause, which I certainly don't have my own. You know, I think that one of the ways in which it's viewed is that there is a metabolic benefit, potentially, to not having the normal reproductive cycle after a certain point of time, in particular, where you have the potential for increased genetic sensitivity or susceptibility, but you also then have species that outlive their reproductive age that have a value of sticking around, right, whether it's this intergenerational providing of care, certainly in the context of more complex species where you have intergenerational transmission of information, which is what we call culture. Right. And so the benefits to that, and the evolutionary forces that might lead one to the other, you know, I think are very, very complicated. But for example, I think that is one mechanism that may explain some, in some contribution to why menopause is involved. And, you know, obviously, it's going to be different in the context of all of the associated physiologic changes that are detrimental. Right. So then what is the the sort of evolutionary cost of that versus, you know, actually just keeping the hormone cycle going?


Nick Jikomes 1:48:30

And my understanding is that there's a few species where you have female menopause humans, I think Wales elephants attempts to be sort of highly social long lived, multigenerational.


Devanand Manoli 1:48:42

Exactly. And I think you're highlighting a very important point, part of it is longevity. But obviously, you need longevity to have introduction, intergenerational transmission of information. And so, you know, if we can start to tease out, you know, if we have long lived species that don't enter it, what are the forces that actually might contribute? You know, another interesting point is, at least when we look at whales and elephants, they're very matrilineal societies, right, or, or coolrooms. And so that may be one of the pressures that sort of evolves to sort of, you know, influence something or sort of the development of these physiologic processes.


Nick Jikomes 1:49:15

Well, Dr. Manoli, I want to thank you for your time. This has been fascinating. I mean, I could I could keep going for quite a while on some of this stuff. Is there anything that you want to reiterate that we went over or anything you want to tie together, we covered quite a bit of ground?


Devanand Manoli 1:49:29

So it's a good question. You know, I mean, I think just, you know, apropos of kind of, like, the most recent stuff that we've been doing it, you know, I think it is actually a really, really cool time to be doing what we're doing. In part from the genetics, you know, exactly where I come from, but also, you know, thinking about how many different factors contribute to something as complicated as attachment right. And now, the fact that we are uncovering that there is this entire I don't want to say Pandora's box, but we've lifted up the hood. And I think that there's a lot of really cool stuff that's going to come out of that and In addition to thinking about, you know, how experienced, you know, one of the things we didn't talk about was, attachment is an experienced dependent, critical period, right, as opposed to many other aspects of development. And so I think that that's going to be a really, really interesting way of thinking about sort of the biology between all of this.


Nick Jikomes 1:50:15

And I don't, I don't normally ask guests for book recommendations. But you know, when it comes to this topic, it's so sort of rich and broad. You know, when we think about social attachment and social behavior, whether it's more on the biological side, or the psychiatric side, or the psychological side, are there any books or resources that you would recommend where people can start to dig into this stuff more?


Devanand Manoli 1:50:34

I mean, you know, to be honest, I actually think starting sort of the original founders of sort of human attachment theory, Bowlby and Ainsworth, you know, they've been there at work is actually incredibly accessible. And then anything that sort of takes that into different contexts. You know, there are many people who have sort of, you know, adapted it. But to be honest, I would actually say some of the original work is, is worth reading, because they, you know, they were presenting theories to people that they really had to convince, and so they did a very good job of both presenting the evidence, but also framing it in the context of some of the evolutionary theories that they were basing it off of. And I, you know, it's rare that I would say go back to the original, you know, because there are many people who sort of distill it, but I actually think that there are some of the few that really did a good job of presenting those theories. And what were those names again, John Bowlby and Mary Ainsworth.


Nick Jikomes 1:51:21

Excellent. Yeah, no, I think that's interesting and interesting recommendation. So again, thank you for your time. This has been fascinating. Professor Manoli Thank you.


Devanand Manoli 1:51:30

Thank you very much. Like I really, really enjoyed





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