About the guest: Marcelo Dietrich, MD, PhD is an associate professor in Comparative Medicine & Neuroscience at Yale University, where his lab studies the neural basis of behavior in mammals.
Episode summary: Nick and Dr. Dietrich discuss: maternal care behavior, mother-infant bonding, and feeding in infant mammals; neural circuits regulating hunger & satiety; brain development & early social learning; behavioral variability among individuals; and more.
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*This content is never meant to serve as medical advice.
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Marcelo Dietrich 1:33
so my name is Marcel Dietrich. I'm an associate professor here at the a school of medicine, and my lab, it's particularly interested in the dynamic change in your circuit that happens throughout development. So from infancy to adolescence to adulthood, how neuro circuits are changing to regulate the distinct behaviors and physiological needs. So that's what we are studying.
Nick Jikomes 2:06
And on your lab website, you have a nice Lab website, you have this video and a quote from a man named Perry Harlow. Can you talk a little bit about what that quote means and who that was?
Marcelo Dietrich 2:19
Yeah. So yes, Harry Harlow, the quote is that if we have learned anything about the studies of monkeys, is that we we have to learn how to love before we have we learn how to live. And it's a long story. I will try to make it short. So Harry Harlow was a primatologist, a behavior scientist who made really pioneer studies in the 50s, 60s. And we can talk more in details if you want, but basically what he was trying to test is, what are the factors in a mother that are relevant for a baby. So he took orphan monkeys. He will actually fly these monkeys from India. He was a pioneering studies rhesus monkey. And then he would raise these monkeys with two type of Wired mothers, one wire mother that has a bottle, had a bottle of milk, and one wire mother that had a cloth. And so the cloth will provide some kind of tactile experience. And the idea was to test the hypothesis that whether the monkeys will like better a milk or tactile experience. Those studies were really mind blowing back in the day, because the monkeys would spend, like 23 hours and a half of the day wrapped around the cloth mother. So they would overwhelmingly choose the cloth mother.
Nick Jikomes 3:48
So so the idea was, well, obviously, the baby needs to eat, and the mother is the source of food. Obviously, babies love to be embraced by their mother and hear the mother's voice and all these things. But when you sort of, when you put, when you put the food, the milk, against the the physical touch sensations of the Mother, you're saying that the monkeys would spend almost all of their time getting that physical touch. They really seem to prefer that. Yeah,
Marcelo Dietrich 4:12
correct. And I think the those findings need to be put in the context of the time of the 50s and 60s, and we can also try to go through that. But I think the most fundamental experiment of Harlow is the following. We have all been a playground with kids, and we see that the kids usually look for the caretaker, for the figure that's around to see if the the caretaking figures around, and then they play. So if the caretaker disappears, if kids flip out, they so Harlow had that intuition, so he did the same thing. He put, he made a playground for baby monkeys, and he put the baby monkeys to play in the playground. But then he put the. Wire mother with a bottle one playground, or he put the wire mother with the cloth. So when Harlow put the babies in this playground and there was the wire mother with the bottle of milk, the babies will not play. They will they will be. They will freeze. They will be in tremendous distress. So that mother provide no comfort for the baby, despite the fact it provide milk when he then switched the mother, but the cloth mother, this baby's monkeys will go hug the clot mother, and they will be playing around. And then often they will look back, see that the mother figure was there, the attachment figure was there, and they will continue playing. So that was really, I think, the key experiment showing is not only a preference, but this, this artificial, inanimate mothers have actually the capacity to buffer the distress of the infant and allow the infants to explore and play and learn about the world. And so, yeah, that's a experiment that I like very much.
Nick Jikomes 5:59
Yeah, and it starts to tell us that, I guess, you know, there's multiple things in an infant's environment that are tied to its mother, that are of interest, that the baby needs. It needs food, it needs safety and to have protector around. It needs that physical touch. But all of those things are not weighted equally to the infant, that some of the some of them are having sort of a stronger effect on the baby,
Marcelo Dietrich 6:23
Yeah, certainly. And yeah, Harlow test that. And I think it's there's a lot to talk about Harry Harlow, but it's probably one of the saddest experiments he did a few as he progressed in his career, he got a little out of his mind and was heavily criticized for the ethics of his experiments. And one experiment that he did was to cool down the mother, so you would have he cooled down two degrees cooler than the room temperature, and ask whether the baby would attach and would get milk from the mother. And this
Nick Jikomes 7:04
is the artificial mother. Artificial, yeah, artificial. And he did. I
Marcelo Dietrich 7:08
think, I believe I might be incorrect on this one, so we have to double check and but I think he also anesthetized the mother and cool down. So if he cools down, this the mother two degrees under room temperature. The infant monkeys will never get close to them, will not get even milk, and they will die. So actually, the title of the paper is psychological death in an infant monkey. Wow, so and, yeah, very sad. So basically, in harrows experiment, he puts temperature as number one of the sensory importance of the mother. And then comes touch, tactile experiences. And then rocking, the movement is important. Milk is actually the last of the series. It's not that it's unimportant, but nursing is the lowest in importance in his experience.
Nick Jikomes 8:09
Yeah, and it's a, you know, it's potentially counterintuitive, right? You might think, well, the baby needs to eat to survive. The mother's the sole source of food. It's a little bit surprising. It's not surprising that it's the tactile sensation and the warmth are all important, but it is perhaps surprising that they're even more important than the food.
Marcelo Dietrich 8:27
Yes, certainly, and that's why I like that quote that's done on my website. Because also, at least, I think, I think if we talk to child psychologists or people that are in that field, they will not find surprising, at least now, but for us, when we start studying, this was also surprising. And I think the concept that's always on my mind, it's the ecological context in which these features evolved. So in here we are talking about mammalian evolution. We have about 6500 mammals on Earth. And all mammals necessitate a mother, a caretaker, to obtain this early, early nutrition and early stimulation. So the way I I think, and I can explain that those harlows findings in an evolutionary context is that the primary importance in the beginning might be the milk, but after millions of years evolution, the mother always predicts milk, hence milk becomes irrelevant. From the perspective of evolution, what is more relevant is the other stimulus. So the the proximal effect, as we say, it's actually touch and other stimulation, but they automate. You definitely need milk, but the correlation is always 100% in nature. Yes, you never get a mother the wild, and if you do. Have a mother, usually that provides no nutrition, the infant will die. So there is no evolutionary adapted selection. It's
Nick Jikomes 10:09
just like applying reinforcement learning within one animal's experience across, you know, millions of years of evolution. You know the the most efficient thing to do is to learn the first thing that predicts the outcome you care about. And in this case, right? The mother, the mother is always around to provide the milk. So it does make sense, when you think about it in that way, from a reinforcement learning perspective, that that evolution would sort of bake that kind of tendency in
Marcelo Dietrich 10:32
No, I agree. There's another animal that I like to talk about, because I think it's just fascinating. So as I say, we we have about 6500 mammals on earth, and the one that we know that has the shortest lactation period is one seal that lives in the Arctic. It's the so this seal the the infant, only the neonate only stays with the mother for four days. So within these four days, we'll gain, like, 200 kilos or so, and so we'll take immense amount of milk, and then the the baby will leave. But the baby cannot hunt on on their own for another month. So they survive, they fast for another month, only eating ice as a form of hydration. So actually, the physiological systems to eat and already. But ecologically, the baby cannot stay surrounding, surround by the mother, because there's a risk of predation. But even we in that extreme evolutionary context, ecological context, the attachment, the relationship of the baby with the with the mother, didn't disappear. It did shrink to four days, but it did not disappear. Maybe we need a few more millions of years to find mammals that in which that bone will be broken. But, you know, that's one of the extremes. Yeah,
Nick Jikomes 12:03
so that just gives a sense for the strength of this bond, and the importance
Marcelo Dietrich 12:08
is very it's basically a constitutive part of being a mammal.
Nick Jikomes 12:13
And, you know, one of the things we're going to get into here is how hunger and feeding work, and how some of the the circuits in the brain, develop that, regulate that, you know, but obviously, just on an intuitive sort of experiential level, obviously an infant has feeding behavior that's very different from an adolescent or an adult. You know, as adults, we eat so many different types of foods. We have to learn what we like. We get to test out all different sorts of tastes and see how we react to it. But for a newborn infant, right? It's sort of all baked in. There's gonna be one food source for some period of time. It's just the milk. The baby doesn't need to learn about the milk really. The suckling reflex is gonna be there right from the start. And as you said, you know the mother, the mother is obviously there when it comes to mammals. That's just part of being a mammal. Can you talk a little bit about how sort of hunger and food and nutritional needs change from infancy to adulthood, and, you know, sort of general ways that cut across all mammals. You know, obviously the milk has a certain nutritional composition. It's presumably tuned to the baby's needs early in life. Then those are going to shift over time. But what are some of the ways, the major ways, and most are all mammals that sort of the food needs and the hunger needs of an individual change from infancy, infancy onward.
Marcelo Dietrich 13:33
Yeah, it's a fantastic question. There's so much to unpack. There so many things come to my mind, maybe, maybe we break down in peace, and you can reflect on what I say. Since we are talking about different animals, different mammals and examples of that, I will continue giving these examples, because I think this one is mind blowing too. So marsupials, some marsupials, so mammals that will have a pouch and the embryo will actually attach to the nipple within the pouch and then grow within the pouch. Some are Supers, will have multiple layers of nipples. So for example, we will have the vagina will have three chambers. So the first embryo climbs from the chamber and attached to the first layer of nipples, and then once it grows, it climbs to the second layer of nipples, and then the embryo from the other chamber will come to the the first layer, so they are synchronized in the climbing the layers, and each layer will have a different milk, which will be important for the growth and nutrition and the immune system, immune protection of the growing infant as it grows in the. Journal pouch of the marsupial man.
Nick Jikomes 15:04
So in marsupials, the embryos developing, and it's always in the pouch, but there's literally different sections of the pouch, and the embryo is kind of climbing through each section as it grows and as it grows while it's still, you know, in the in the pouch in the womb, I guess it's attaching to different nipples and the composition of the milk in each nipple is actually different
Marcelo Dietrich 15:24
Exactly. So I give that example to illustrate this remarkable features is the same other different nipples, each nipple with the different milk composition. So what we do know is that new composition chains throughout lactation in animals and primates and humans, and that match the nutritional and also the other needs. For example, milk will have many antibodies that will be important for immune protection of the infant early on, for example, IgA, that's mucosal antibody will be very high early on, and then we will start paid as lactation goes on, as also the infant start produce their own levels of antibody. So there are all these features that are matching the physiology of the infant. So if so that's talking about that. So
maybe you Yeah, maybe you
Nick Jikomes 16:26
Yeah. So, so basically, I mean obviously, obviously, the nutritional needs of a baby are different than an adult. But what you're saying is, like even within, even within the preterm period, even within early infancy, the infancy, the nutritional needs are changing. So the composition of milk, you know, from when a baby is born on day one will be different, you know, just a few weeks or months later. And that's all tuned to the baby's needs. There's the nutritional needs, there's the sort of immunological effect here. Before the baby can prove its own antibodies, it's literally ingesting them from the mother. And so all of these things sound like they're sort of beautifully orchestrated to perfectly match what the baby needs each step of the way.
Marcelo Dietrich 17:06
Yes, certainly. And so you know one.
And then the question you ask also the question about regulation, right? There's a regulation of feeding in adults. Well, the that we know quite a bit about that, and how is the ingestion regulated in an infant or in a new need, we don't know fully that's the real the, I think the most accurate answer. And there are many theories of whether breastfeeding and intake of solid food, for example, utilize same neuroscircuit same brain processes, or parallel brain processes and things like that. So we still don't know the answer to that. However, we know a few things, mostly from rodent models. I would say rats, mostly, some work in mice that very earned in development right after birth. There, the neonates don't seem to have a mechanism to stop ingestion when they are ingesting like breast milk. In other words, if you take a infant rat and the infant attached to the nip of the mother. But instead of getting milk from the nipple, you pump milk in the mouth, this baby will ingest constantly, until almost literally exploding, Oh, wow. We only stop when the stomach is in huge, huge, huge age. So they
Nick Jikomes 18:55
it sounds like that in the infant rodent, at least the satiety mechanisms that are developed in an adult are not there
Marcelo Dietrich 19:03
yet. Yeah. So when, again, when you put that in perspective of the relationship of what is happening in breastfeeding, it makes sense from the following perspective, the regulation of the intake is actually done by the milk ejection reflex. And the milk ejection reflex is not constant. In fact, when the baby is attached to the nipple, is stimulating the sensory neurons in the nipple in the rat. People have done that experiment, the ejection of milk from that stimulation is going to be a random event, really, within, within a certain distribution of time, yeah, within 30 seconds to three minutes or four minutes, I don't remember exactly the data, when the milk is going to be ejected. Is a random probability. Yeah. And I think that's really fascinating, because you remove the need for the infant to have a regulatory process, yeah, again, the same evolutionary process. There is no need for regulating because there will not never be enough. And whatever comes comes, it comes with the timing that's definitely sufficient for absorption, opening the stomach, going to the lower gut, and getting more milk, more milk. So the mother regulates the process. Again, you give to a third party the regulation of the self,
Nick Jikomes 20:36
yeah. So, so, so when you see an infant mammal suckling milk from its mother. It's not actually getting a con. It's not like if we, if you and I, were to have a cup of milk with a straw in it, and we can constantly suck it out at a constant rate. It's that's not what it's like. The milk is sort of coming out haphazardly. And this is actually serving, uh, an adaptive function. It's preventing the the baby from ingesting too much, essentially, exactly,
Marcelo Dietrich 21:02
and that's one part. And the other adaptive function is when the baby's there, in the breast, in the nipple, many other things are happening beyond the ingestion of milk, much like the experiments of Harlow. So in that in that moment, for example, when you record the autonomic nervous system of an infant, the autonomic nervous system, the sympathetic tone of a baby, is much more regulated, is much calmer when it's attached with the mother, so the baby
Nick Jikomes 21:39
feels safe, the stress levels go down. The baby's presumably not anxious or anything.
Marcelo Dietrich 21:44
And in that context, the baby learns. In that context, the baby's so it counts, stress response is low. The baby learns about the environment very early days, we learn all the associations. We start learning sound associations. And then when visions start to get better in the human baby, we start learning facial expression.
Nick Jikomes 22:07
Yeah, and this would imply that, I mean, there's a lot you could unpack here, and there's a lot of things you could think about in terms of, you know, modern human caregiving for infants and stuff. So, you know, just ask you one thing here, you know, you could imagine two human babies. One of them is getting breast milk directly from the Mother, the natural way and doing things the natural way. Another one, you could imagine giving an infant formula from a bottle, same nutrition value, same calories and everything. The implication here is that baby would actually have some learning deficits, maybe because they're not going to have this change in the sympathetic nervous system that's going to affect their stress levels and that's going to have knock on effects for their ability to learn faces and to become familiar with their environment.
Marcelo Dietrich 22:53
Yeah, it's absolutely a generalization, but I think is fairly correct, and I think, sadly, we learned quite a bit about that process from, I think your audience is familiar with that, probably the Romanian, Romanian orphanage. So in the late 80s, with the fall of the Berlin Wall in Romania, Romania in the 80s, was in an economical crisis, so need more babies. So there was a governmental communist incentive to have more babies, so families will have a lot of babies. And there was a selection process, so babies that were kind of misfit were put like in this warehouse, so they receive nutrition, but really no stimulation, no caretaking. And so when scientists got there after the the fall of the dictatorship, they found this, hundreds of 1000s of babies. So there was nothing that could be done. There were no families to adopt all these babies. So they run the the only clinical trials that we probably will ever be able to run, which was selecting some kids and give to foster care. And what we learned from that, that if you do take
infants
during a sensitive period, roughly the first two years of life, and you provide that care, that comfort, that tactile stimulation, they will develop quite well. But if deprive them so, if you only give the bottle you suggest, then this infants will develop with very severe, uh, neuropsychiatric symptoms and social deficits, impairment, capacity to socialize. Yeah? So, yeah,
Nick Jikomes 24:53
wow, yeah, yeah. So that that early period development is is super important, and it's not just the sort of raw. Physical needs of the body in the form of, you know, getting food and hydration and stuff. It's all of this sort of these, these sensory and social effects that put the nervous system in a state that actually just enables learning. Generally, if you don't have that, you're going to have all sorts of problems. Yeah.
Marcelo Dietrich 25:19
Yeah, absolutely, that's
Nick Jikomes 25:24
And so you've, you've done studies in in young rodents that have to do with disentangling how the feeding system develops and things like that. Before we get into some of that work that you've done, I want to give people a general sense for how the sort of hung we'll just call the hunger circuitry in the brain works in an adult first so I'll let you sort of take it where you will. But the hypothalamus is going to be a very important brain region here, and there are specific neurons in the hypothalamus that that are really, really cool and really important here, that drive hunger and satiety. Can you give us a basic understanding for what some of the key circuitry is that controls hunger in mammals, in adult mammals,
Marcelo Dietrich 26:06
yeah, absolutely. And I will certainly focus on on the hypothalamus, because I think we make sense for our discussions later on. So in the actually the most basal part of the brain. So above our palates, our soft palate, they will be our pituitary, the gland they regulate many of the hormones, like HPA, stress response, and right above that, there's a layer of thin skull, and then the hypothalamus. So they have in the very base of the brain and the nucleus, the part of the brain that's the most base, that was called the archway nucleus in the in the humans, in prime is the infundibular nucleus, and in this region there are some neurons that are important in the regulation of feeding and metabolism. We start to suspect this more than 100 years ago, because that region, the pituitary gland, is commonly, commonly affected by tumors. So the tumors go and because the hypothalamus is right there, it pressures the hypothalamus, so you start causing some people have symptoms in energy metabolism, obesity or things like that. So in the 19th century, people start to suspect about the role of the hypothalamus in feeding. So fast forward 100 years, we know there are two populations of neurons there. One is called AgRP. HRP comes from a good related peptide, a good related protein, which is a gene, the AGP gene that produce this peptide by these neurons. And when these neurons are activated, or when the animal is deprived of food, these neurons will be activated, and they will promote feeding and many of the metabolic responses to fasting or to food deprivation. Next to these neurons, there's a second population that's called palmci neurons. They produce propio melanocortin, and the propial melanocortin is a large molecule, large protein that can be chopped in several small peptides, and some of these peptides have strong satellite effects like Msh alpha, SHM and also Beth endorphin, which is an opioid. So the palm syndromes are taught to be the counterarm of the AGP neurons having a little more delayed effect, but when they are active, they promote satiety, and AgRP neurons, when they are active, they promote hunger. That's an overly simplification, but I think it's a bare one. So,
Nick Jikomes 28:56
so a bit of a simplification, but in essence, at the bottom of the brain, in what's often referred to as the arcuate nucleus of the hypothalamus, there's two neurons. And basically, if you turn on one type, type of neuron, the HRP neuron, animals look like they're very hungry, they will eat a lot, etc. Then if you turn on the other palm C neurons, you basically get a counteracting effect, exactly. And so, so naturally, you know, you would think, you know, what do we know about these neurons in terms of their activity? If you've got sort of a hunger neuron type and a satiety neuron type, you'd imagine that turning on, say, the age of appearance, drives feeding behavior, that when animals are hungry and they're looking for food, those neurons might be very active, etc, etc. Is that essentially how they work?
Marcelo Dietrich 29:38
Yeah, it's, yes. That's a
so in the early 2000s
was shown that the AGP neurons were response in that predicted manner. You feed the private animal, you have increased activity of AGP neurons. You feed the animal back and the activity to decrease the Tech. Nix used back then were markers. They have a very slow dynamics, which means matter of hours to find those activity chains and in 2015 using new technologies, basically three labs, almost simultaneously. Scott stern so Janelia farms, Mark Anderman at Harvard, and Zachary Knight at UCSF. Using three distinct techniques, they were able to record the activity of these neurons in the live mouse, and they actually show that once the animal actually sees the food or perceives that the food is available in the environment, the activity of these neurons will suppress, will decrease in an infecting anticipation of eating after eating, there's a further suppression that comes from gut signals. But that that anticipatory drop was something that was somewhat unexpected. If you think, like, only we call omniostat, like, if you're changing your temperature in the house and but like, 72 and so the thermostat we want to switch on and off at that point. But here you're saying that, as is reaching, is predicting Yes, yes, future. So it's actually switching anticipation to Yeah.
Nick Jikomes 31:25
So if Yeah, you're saying, if these neurons were merely regulating hunger in a purely, like homeostatic fashion, they would be pretty simple. They wouldn't start to change their firing until an animal eats the food and the calories get into the body, and they're actually, like, ingested but, and that does happen to some extent, but what you're saying is, when an animal, even hungry animal, even sees food, these neurons are immediately responding, and so they're doing something more sophisticated and complex that has to do with, you know, understanding that food is about to come even though you haven't actually ingested it yet.
Marcelo Dietrich 31:59
Yeah, absolutely. I think that comes back again to the complexity of the brain and of mammalian systems in general that we are not dealing with engineer like machine that turns on and off, and it's a much more complex system in which one of the main advantage of this complexity is really the capability to predict what's going to happen at different timescales, seconds, minutes, hours, days and so And that really gives a lot of adaptive value to the system, because, yeah,
Nick Jikomes 32:45
and, and, you know, oftentimes the caricature that people have of the hypothalamus is it's deep in the brain. It's part of our so called reptilian brain. It's sort of a stupid area of the brain compared to maybe the cerebral cortex or something like that. What does this start to say about, you know, the sophistication of the hypothalamus and how much that's been maybe underestimated over time, and to what extent do these circuits actually tie into learning and memory systems that we think of as being higher up in the brain? Normally?
Marcelo Dietrich 33:18
Wow, that's a very good question. I'm trying to think how to answer this question without diverging too much, because I think there's a lot to unpack in this HRP,
I think one way that I can answer, I think some of we still don't know fully, that's I think it's a fair answer of how these hypothalamic circuits, how they interact with higher order learning circuits. Now let's say an animal sees a sound that sound has no predictive value. It's the first time the animal sees the sound. Yeah, the age opinions will not do anything you record the activity, they're not going to
Nick Jikomes 34:08
do anything. They have no relevance to food. And so then
Marcelo Dietrich 34:11
you pair that sound with food. You give the food. So every time the sound rings, there will be food that will come with the right after so then when you give the sound, the EGP neurons are going to start to respond. So there's definitely a learned component. So the end was learning that the sound now is a predictive cue of food, and that cue is actually coming from higher brain orders sensory systems all the way to the AGP we know a little bit about the circuits that engage that cue evoked suppression of the AGP activity. However, we don't know fully yet how the this memory. Yeah. How the memory of that context is actually going all the way? And I think that's a very important question, and I think there are many laboratories right now trying to actually figure that out. Yeah,
Nick Jikomes 35:17
yeah. But I guess you know, at a high level, the circuit is not purely responding to hard coded, instinctive food related things. It is actually receiving information that's learned through experience.
Marcelo Dietrich 35:29
100% Yeah, 100%
Nick Jikomes 35:34
and so what happens? Just to give people a little bit more sense of how important these neurons are, let's say you take an adult animal, and I know that there's ways to do this, and we don't need to go into the technical methodological details, but scientists have the ability to say, destroy HRP neurons in an adult and people have done this, what happens if you destroy these neurons in An adult animal?
Unknown Speaker 35:56
So
Marcelo Dietrich 35:58
is another good question. It's, the findings have been a little controversial in the last couple years, but I would tell you the the originally in 2005 the laboratory ritual parameter, they create a transgenic mouse line that allow eliminating the AGP neurons in the brain acutely. So expressing the receptor for differ toxin, diphtheria toxin, so when you give the toxin, will bind to the receptors in the AGP neurons only, and kill these neurons. When he did that the animals will starve to death with within a week. And so that was thought to be the case until recently. Now, when he inject, did the same procedure in a 2345, days old animal, so I knew Nate, nothing happened. So originally in his paper was a paper published in Science. I remember vividly the day I the paper came out. And so what started entrepreneurs were essential for feeding in the adults, but not in the units. Now that also has been put a little bit in check recently with another study that used several of these techniques and said that maybe the effect of the ablation had some indirect effects. Was not exactly by killing the AGP nearest.
Nick Jikomes 37:41
So it wasn't fully, maybe not a fully clean experiment. It was doing something other than ablating The AgRP, maybe.
Marcelo Dietrich 37:46
And it's a, I think it's a very, it's still very controversial, because many people have replicated those findings. And, yeah, I think these techniques all have their caveat. Now, in general, if you don't have AGP neurons or inhibit the AGP neurons, the animals will at least have a deficit. Yeah, they eat less. They will have a death in eating. If you food, deprive them and give food, they will have less of that effect. So in general, that's the
Nick Jikomes 38:19
yeah and, and, I guess in any case, you know technical issues aside, one of the key results there was that you see a big difference in the type of effect you get in babies versus adults,
Marcelo Dietrich 38:32
absolutely.
And they're always stuck to me in my brain, and it was one of was a key finding to stimulate us many years later. So I start my lab in 2014 and I was interested in that question, though, what regulates the intake of breast milk, of calories early on, if you can, if you can, kill the Egypt and nothing happened, yeah,
Nick Jikomes 39:06
and I mean, immediately I'm thinking of what you told us before, where the the baby, there's this mechanism in place in the mother to make sure that not too much milk comes out, because the baby actually doesn't have the ability to self regulate its intake. And so that would imply that the maturation of certain parts of the brain that have to do with feeding and satiety takes time and has not developed in the early infant.
Marcelo Dietrich 39:31
Yeah, absolutely. Yeah. This concept, it's much clearer to me, and I think to us in general, today than it was 10 years ago, but that was somewhat what we tried to test. Basically, we asked the question whether this AGP, neurons that promote hunger would regulate the intake of breast milk or will have any importance for the injection. Positive Behavior of infant that's still in the full dependency on the mother. So the mother is the regular regulator. And so we did those experiments right when I started the lab, trying to play with the neurons, activating the Egyptian neurons, inhibiting the Egyptian neurons. And it was quite striking that we would find no change in ingestion of breast milk, for example, if we doesn't matter what we did with the neurons. But when we would play with the neurons in the babies, for example, in an infant mouse, there was a long we could make these babies cry more or cry less. So the infant mice vocalize in the ultrasonic range, and so we could have really big effects on the amount of this cry behavior, or the amount of ultrasounds that the babies will emit when they were alone. And we thought that that was quite interesting. And those ultrasounds are known to function as a cry, which means, if the mother listens, the mother comes, yeah, yeah to the mother.
Nick Jikomes 41:18
So, so just to unpack a couple things here before you continue. If you take an adult mouse, yeah, and you turn on the HRP neurons, but there's no food around, they will start looking for food. They'll sniff in the air. They'll dig through their bedding. They'll they'll search around for food, and they it looks like they're trying to find food. If those neurons are active and there's food around, they'll basically stop what they're doing and eat it. But what you're saying is, when you do this in an infant, what it starts doing is basically calling for its mother,
Marcelo Dietrich 41:48
exactly, they call for their mother and and then we did the
sequence was more or less I'm telling the sequence that we did the experiment. So then we we look for if these neurons were active when the infant is alone, right for the mother. And actually they get very activated. They are very active as much as one would predict after depriving adult from food for like a day. So we were very surprised to separate the baby from the mother for half an hour, an hour, an hour and a half, and the activity is very high. Again, we've first we use these techniques that have no temporal resolution. And so the neurons were active, and the infant is alone, the AGP neurons, and when you inhibit these neurons, they cry less. When you over activate them, they cry more, and that changes the mother behavior. And then we took some of these techniques that I mentioned, that these labs used in 2015 and then we applied them to record the infant mouths, which is quite tricky, because infant mice are very small, and they grow from one day to the next. But yeah, I also remember those experiments, and basically it was quite striking when we are recording the neurons and the infants are with the mother, with the siblings in the nest, the neurons are quiet as soon as we take everybody out and they are alone, the activity of Egyptians start firing immediately within seconds. So it's a very rapid effect. And as soon as we put any social partner back with the siblings or the mother, the activity suppressed to what it was before separation, within 30 seconds. It's a very rapid alarm system, like turn on, turn off, that's very different from what we understood from how the activity of these neurons is modulated in the adult, because in the adult, the activity is slowly increases as the animal is deprived of food.
Nick Jikomes 43:59
Yeah, yeah. It's a slow signal that's tied to basically how hungry the animal is, yeah,
Marcelo Dietrich 44:03
and here is within seconds. So, and what was interesting, the experiment that we did, very, very much inspired by Harlow, was separate baby mouse activity of the AGP neurons is high, and then put it back different kinds of foster mothers and see what is important for suppressing the activity of the
Nick Jikomes 44:32
and I guess naturally to anticipate some of this, naturally knowing what we knew about AgRP neurons and the relationship to hunger, these are, you know people call them the hunger neurons. Basically, you might predict, I might have predicted, I think, that if you took the baby away from its mother, the mother predicts food for the baby very reliably. So the adrenals become more active. And if you then give it milk without the mother present, the neurons might get silent again, because the AgRP neurons are. Supposed to be all about hunger, exactly.
Marcelo Dietrich 45:01
So we did that the exact experiment that you said. So we pump milk back. Basically was an experiment that we have to take mother's milk. So we pump milk from the mother and give the milk back for the pub. So the pump will just their own
Nick Jikomes 45:18
milk. Yep, they're getting their natural mother,
Marcelo Dietrich 45:21
natural mouse milk. So we did that, and we also did a cow, whole milk from cow to have a different source of calories to control for that, and milk didn't suppress the activity of the neurons. So the babies, we filled the we filled their stomach while they were alone, and he did not into the activity of the neurons. And then we were puzzled, because he broke the broke our instinct. So
Nick Jikomes 45:46
these neurons remain active, the so called quote, unquote, hunger neurons remain active even though the animal's not hungry anymore, because you just gave them all the milk that their stomachs
Marcelo Dietrich 45:55
could hold. Exactly. It was around that point that the student that was with a grad student that was working my lab. His name is also Marcelo Marcel Zimmer, so we call him m2 and we were puzzled by that data. And then reading Harlow and all those studies, we say, how can we test that he was then, that we did the experiment that I was going to tell you before we isolate the infant, and then we gave different foster mothers. So instead of milk, we provide different forms of caretaking behavior. And we thought first we would provide a foster mother that we the mice, like females, when they are not lactating, the nipples are not protruded, so the mice cannot attach to it. They don't have nipples that the baby mouse can attach. But if you take a grandmother type of thing, they will have no nipples. But they are caretakers, so they really
Nick Jikomes 47:02
still feel the warmth of the Mother, the feelings of her fur, the tactile sensations, but there's no nipple to attach to.
Marcelo Dietrich 47:07
They will leak, they will groom. They will do everything that a mother will do, but there is no attachment to the nipple. So one type of foster caretaker was the grandma. We call the grandmother, the other was female. We know from our own experience with influence, but also from the animal research and the animal world that what's called the pacifier effect, and infants that's alone is in a distress. You give a pacifier, you stimulate the mouth and that calms down the baby. I often give that example for bat orphanage. In bat orphanage, one great way to raise bats that are orphans is actually to give a pacifier. They grow badly, so we thought that we need to give a pacifier to see if a pacifier will pacify the Egyptian. So one foster caretaker was a female mouse that had nipples, so now the babies could attach, but the nipple produced no milk. We experimentally generate that kind of female mouse. And the third type of foster caretaker was another mother, a different caretaker that had nipples and had milk. And then we asked which of the mothers will cause the largest inhibition against the prediction being that, if these neurons are hunger neurons, the presence of milk should suppress when it comes from the natural environment, the breast, when we pump, we had no effect, because was artificial, and the results were striking. If we give a caretaker a grandmother, no oral stimulations, just caring, we suppress the activity of the Egypt it was, let's say, 30% if that foster caretaker has nipples, therefore oral stimulation we suppress, let's say, 80% now, if the foster caretaker, if has nipples and milk, is still suppressed, 80% the presence of milk has no effect in further suppressing the AGP neurons. And that was really remarkable at that time, because you say, Wow, it's really it's that concept that we discussed before. It seems that the milk is insignificant to modulate the activity of this hunger neurons during the sensitive period of life in which caretaking nutrition is coming from the mother. It's being related by the mother. Yeah,
Nick Jikomes 49:42
yeah. So, I mean, it is sort of gets this idea that these neurons, they're obviously about hunger, but it's less about it's not completely about the presence or absence of calories. It's about the presence or absence of sensory stimuli that will predict whether you can acquire those. Things. And although this is counterintuitive from one perspective, based on what you said before, if you think about it in evolutionary terms, from an infant, you know, there's a 100% correspondence between the presence of the mother and the presence of the milk, so it sort of makes more sense that it would be sensitive to these predictive sensory cues.
Marcelo Dietrich 50:15
Yeah, absolutely. I think that's that's correct. Of course, there's some experiments that we haven't done and they should be done and they are very difficult to do. Yes, yes, hence why they haven't been done. And one alternative, so what you just said is the evolutionary explanation that we discussed before. So breast milk becomes irrelevant. The mother is a predictor. Hence, the proximal signal for the infant is the presence of the mother the milk. Milk has no regulatory function. Another explanation will be what we will call developmental explanation, or onto genetic explanation. It will be somewhat like this, the infant, the EGP neurons actually are responding to deprivation of nutrients, or, let's say, a metabolic challenge, yeah, that's somewhat similar to food deprivation, and very early, the mother provides the milk so fulfills that need and provides all of the sensory experience the animal learns, learns so rapidly, so strongly that for now only, only Use the proximal learning cues, and doesn't use the nutritional cues anymore because they are irrelevant. So we'll be, it will be that same evolutionary concept, but now placed in a developmental concept. So from birth, from birth to that point. So then we learn that contingency, learn that pairing, and now is not using the breast milk as a as a cube, so we don't know that. We don't think that's the case because of all these studies that I told you, but it's very hard to prove that something doesn't happen or something doesn't exist, and I think they're really the experiment that will be important to do is to be able to raise these infants in the absence of a mother, for example, with an artificial care to us, bottle feeding them from birth and then uncoupling maternal caretaking from ingestion, and see what happens. The problems with that, those are very challenging experiments to doing animal models. Second, when you do that, you cause a lot of collateral damage, because you, you are, you are breaking a contingency. That's, as we said, from the high roads work and others, is very important for development.
Nick Jikomes 52:57
Yeah, so, but I think another thing that's a little tricky here too, is we're talking about rodents. So they're smaller creatures. And obviously baby rodents are even smaller than adult rodents, and their metabolism is very fast, and they're very sensitive to, you know, things like temperature. So I would imagine that at least in principle, the brain of an infant's probably gonna learn early on that when you're detached from the mother, obviously you're you're away from the source of milk, but you also immediately have considerations, you know, for like hypothermia here, and so the brain could learn very quickly, when the temperature drops, I'm about to be nutrient deprived because mom's not around, or things like that,
Marcelo Dietrich 53:41
yeah, the way we think is very similar to that, but it's broader in terms is not only nutrient deprivation, but it's as is a metabolic challenge in general, the infant, if needs to produce more Heat, right? Will be a net. That's it. And originally, when we published that study in 2019 now, five years ago, we did test that idea that temperature was a an important component of that it is so. And how did we do that? Basically, remember, if we socially isolate the baby mouse, AJP neurons, the hunger neurons, quote, unquote, are highly active. So what we did was to provide a warm environment. If you provide a warm environment, that's the temperature of the nest, then you prevent that activation, or you block substantially that activation I see, we also did an experiment to test whether there was learn. In other words, did they learn that when they are alone, it's cold and that generates a temperature shock that needs to amplify metabolism. So it's a learn. So. What we did was to raise but mothers at thermonuclear temperatures. Thermal neutral is when you don't need to produce heat from your body to warm yourself up. So we raised mothers at the at 35 Celsius, so the temperature of the nest. They delivered the babies at their temperature. So the babies never saw anything lower than 35 Celsius. So they were always warm. They never had to produce heat. And 10 days later, around the time that we always that we did the other experiments, we separate them from the mother,
Nick Jikomes 55:32
yep, just like you did before, but now temperature is not a variable, yeah.
Marcelo Dietrich 55:35
So we separate at 35 Celsius, so they are just alone, or we separate them at the colder temperature, room temperature. So if we put these babies alone at 35 Celsius, we have a very minimum activation of the neurons, really, really, really minimal. So almost no activation. If we are if we put the babies at room temperature, we have an incredible activation, so they don't need to learn. The contingency is something that the system is capable of responding without experience in their gut. And
Nick Jikomes 56:13
so if I'm hearing you correctly, I think this is what you're getting at a moment ago. It's as if the neurons are anticipating metabolic need. And obviously, food is an important thing related to your metabolic needs of the body. But it's it's not the only thing,
Marcelo Dietrich 56:28
exactly so temperature, other forms of for an infant, very likely temperature is one of the primary needs for the infant, given what you said, they have high metabolic rates. And even the work of Harlow, as I said before, I think speaks to the fact, because when he cools down the mother, the babies would not attach to the mothers. So temperatures seems to be an experience or heat from the mother, a sensory modality that's very important for the infant. And sort
Nick Jikomes 57:07
of, you know, given everything we're talking about, how, you know, hunger, needs and development, mental needs change at different phases of the lifespan, I would imagine that a lot of the circuitry changes or develops around a critical period, which I would guess for for this would be around the time of weaning, because that's when the animal stops needing its mother for milk and it can start eating solid foods. Do we Do we know anything about if the CIR, if the circuitry is changing around that time, or anything like that?
Marcelo Dietrich 57:40
Uh, yeah, we know a little bit about the circuitry change, but I would say definitely not enough, and we have follow up work that some published, but I'm happy to share that touch, touch, some on this issue. So on the circuitry, we know actually that the AGP and palm seed this feeding satiety neurons, they have a lengthy development so they would in the mouse world, they will develop all the way up to five, six weeks after birth, which means that's middle to late adolescence. So they will be increasing projections, axons, going to places they will they will have more synapses into post synaptic areas. So that process is ongoing for all these weeks now, most of the places that we receive a projection, for example, from the EGP neurons, so a post synaptic brain area, we already have a connection in the second week of Life, but some of these connections will be very weak, so they will be increasing in density as the annual age and goes through adolescence. So we know that's so we know a little bit about that. So we also had that prediction that the winning when they are independent of the mother, so they don't need more the warmth, or any of that should be a moment in which this response to the social environment, one would say, would not be significant for the activity of this 100 hunger neurons anymore, or this metabolic neurons. So we have been working on that question since then, for like, five years now, and it's very surprising. So if we take an adolescent's mice, and now we socially isolate this mice, let's say a mouse that's in early adolescence, 2528 days old, haven't seen the mother for a week. It's. Are eating on their own. We separate this adolescent mice for a couple hours from their siblings, and when we separate them, we give them food. So if they want to eat, they can eat. They can do whatever they want. We see the same activation of the age of opinions that we saw in the babies. So actually, the effect doesn't go away. The effect only goes away in late adolescence, when they in the last stage of maturity, sexual mature, when they really become sexually mature, and potentially when there is a switch. We can talk more about about the value of social behaviors. So we still don't fully know the mechanism. That's that, that those findings are actually unpublished and but it goes beyond winning, which is quite striking, actually. Yeah,
Nick Jikomes 1:00:52
another thing I'm interested in here is so as with any circuit, right? There's ways for hunger and satiety circuitry to develop in a healthy or normal or natural fashion, and then, obviously, things can go awry. And there's many ways for brain development to go awry. Some things that come to mind here that you might know something about maybe you've done experiments on, are, you know, I imagine there's a lot of individual variability, even in something like maternal care behavior, you know, we we see that in the natural world. I would imagine that some mouse mothers are very attentive mothers. They're always there. They're rarely separated from the pup. There's always there to allow the pup to suckle when it needs to. Then maybe some other mothers, you know, leave the nest more often. They're separated from the young more often. And there's also a question of, say, variability in the mother's diet, the composition of the diet, and how that affects the maturation of their pups, hunger circuitry. Do we know anything about how any of those variables can lead to, say, abnormal development in the hunger circuitry? How, you know, maybe the absence of enough maternal care behavior or the absence of certain dietary components might lead the hunger circuitry to actually develop in ways that are, you know, maladaptive, that leave the individual vulnerable to metabolic syndrome or something like that?
Marcelo Dietrich 1:02:05
Yeah, wow. Amazing questions. Nick, a lot to back there, so just to myself, rephrase you now try to understand if there's anything out there that we have them or others trying to understand variability maternal effects and how that affects the development of the circuits. Yes, we have, we have not done those experiments, but to lines of research or findings come to my mind. All of them relate to nutrition and diet or availability of nutrients. So the first is to, as you said, to switch the diet of the mother. For example, in in the mouse world, we switch to a diet reaching fat, and so a high fat diet, so the animals will put more weight and things like that. So if you do that during lactation in the mouse, that's the work of Jens Bruning and Max playing in Germany, if you so, the sensitive period seems to be lactation. So if the mother is eating a high fat diet that impairs the development of the agrpineurs. So the impairment means there's less projections of these age opinions to some key target sites or post synaptic sites, and that's in those infants they now now grow. When he puts them on a high fat diet, they will become more obese. So it seems that the diet of the mother affects the development of these neurons and leaves a mark that will affect how the infants will respond. I
Nick Jikomes 1:03:53
see. So if you give a mother a high fat diet during lactation, that's presumably affecting the composition of the milk. And therefore, what the infant is ingesting, when people do that experiment, it affects these AgRP neurons, the density of connections to other brain areas. And then if you let those baby mice grow up, they're then more prone to develop obesity if they have a high fat diet themselves, exactly. And
Marcelo Dietrich 1:04:21
a second, second
experiment that was done
to cause over nutrition in the mouse world. For example, a mouse mother will have an average seven babies, eight babies, 10 babies. So you feel when the babies are born, if you cut the leader to like, three babies or something very small, they will have a lot of milk available, because now there's no competition. So in that way, you can have a model of overgrowth. They will, they will. They will grow quite a bit and put a lot of weight. Right? So there's a phenomenon that happens on the Egyptians. Gets a little complicated, but it's very elegant. So this is this hormone, leptin, produced by the fat discovery 1994 by Jeff Friedman, leptin. So when there's a lot of fat, leptin is high. Leptin suppresses the activity of the EGP neurons, so it should decrease this hunger state overall. That's a simplified conceptual framework. Now the interesting thing is that leptin levels are very high in infants in the first week, second week of life, and that leptin during that period, that leptin actually doesn't inhibit the AGP neurons the left and activates the EGP neurons, so it has an activatory effect. And that effect of leptin on the Egyptian neurons, activating the Egyptian is important for the axons, for the synapses, for the neurons to grow to post synaptars, that was a very elegant work of Richard simmer. So I'm saying that because leptin activates the neurons and then suddenly switch to be an inhibitory signal, because the neurons start expressing a particular type of potassium channel. So there's a shift in the expression of channels in so
Nick Jikomes 1:06:25
at some point in development, these neurons start expressing new channels, and something that used to activate them, leptin, a gut hormone, is going to come to inhibit them after they cross that key threshold
Marcelo Dietrich 1:06:35
Exactly. So the work of Laurie zelder at Columbia, she showed that in the model that you can do this overgrowth, having like three babies being raised by the mother, so now they have over nutrition. You can actually shift the point in development in which that particular channel start to express, or leptin, you start to be that inhibitory signal early on. So you you can shift in a couple days in the mouse that so I'm telling you that, as there is plasticity, one would say in the system, the system is responding to the environment in many ways, we know very little. We still about it and but it's that there's definitely a lot going on there that will leave marks in the way the circuits are working then in
Nick Jikomes 1:07:35
the future, yeah. And so it's very easy to imagine that, you know, if the mother's diet changes, its composition, her leptin levels will be different. You could have something shift when this sensitivity to leptin switches in the baby, and all of these things will, in different ways, affect how these AgRP neurons are growing and how they're hooked up to other brain areas, and then naturally, in the adult version of that animal, that's going to affect how they respond to food and their feeding behavior and
Marcelo Dietrich 1:08:00
all that, exactly. And so, yeah, that's where we are at. We don't know much of those regulatory mechanisms, but we have these examples that tell us that it's a there's a lot
Nick Jikomes 1:08:12
going there. Yeah, do you? Do you have children of your own? No, no, but neither do I, but it's still, nonetheless, I'm naturally thinking about a variety of things for humans right now, all this work that you've done to look at the maturation of the system, the relationship between the mothers and the infants, the importance of the different sensory stimulating, the whole context for the learning of the infant, and how all of these things regulate, regulate development of of of the animal. What does that start to make you think about when? When you think about things like, you know, human breastfeeding versus bottle feeding, versus all of the sort of artificial things we invent for babies to give them, sometimes, in place of what would otherwise happen naturally is that, is that something you've thought
Marcelo Dietrich 1:09:00
about that's a very dedicated topic, and I'm not a special list to actually give a thoughtful answer to that. What I think and what we have learned, I think, from anyway, studies and from a very large body of human literature as well is that the stimulation of the infant, the caretaking that's very important for the neurodevelopment. So even in the absence of natural breast milk, for instance, it's it's the infant is can develop normally by receiving all the all these stimulations they need. It seems to me that the most critical part is to deprive the infants from the proper stimulations that they need. Mm. There is there's an example that I like a lot. Let me try to remember the details, but it's fascinating, because during World War Two, one of the last places for to achieve peace was okay now Ashima in Japan. So when the so the American army was there, the island was obviously devastated
and
and they noticed something that was striking to them, to remember, that's 1940s before Harlow experiments and all of that, all of the above, uh, they noticed that despite the devastation, there were no psychiatrists in the island. There were no no such a thing as a psychiatric hospital, and people were really mentally stable. Hm, uh, they just came from a war. Many people were injured, and there was no much, not much going on in terms of psychological they just went
Nick Jikomes 1:11:13
through this major trauma. But no, it wasn't like everyone was walking around with severe PTSD,
Marcelo Dietrich 1:11:19
and back in the day, half of the beds in American hospitals were were for mental health. So mental health had a huge cost. So they were really puzzled by that, and so they made a movie. They film Okinawa Shima, and the movie is called the ok nouns. And in this movie, they show all this data, and they say there is only one thing that we have observed that we can think that is what's causing this psychological stability or strength of the Okinawans. And it doesn't seem to be a change in diet, a change in genetics or anything like that that compares to folks in the Western world, but it seems to be the way that the Okinawan newborns are modern so for the first two years of life, the Okinawans are fully under caretaking of their mother, 100% so every sign the mother will pay attention, will take care of what the Baby is in need, and often will give the breast for both nutrition or not, as a calming effect from two years old, old, the oldest daughter, if there's no if the the family has the baby doesn't have a oldest daughter, it will be somebody else, cousins or other siblings that will take care of that infant from two to five
Nick Jikomes 1:13:04
years. So there's always there's always someone around in the nest. There's
Marcelo Dietrich 1:13:08
always somebody around in the nest. That baby will never be in the playground alone. And then say the only explanation that we can find for the psychological strength of the Okinawans is the fact that they have this strong relationships and they don't have any distress or adversity, so they can control their emotions fully. And that was a really remarkable finding. It's a it's a beautiful movie. It's an which anticipates all the experiments of Harlow and attachment theory and things that we are talking until now. So I think that kind of findings that we know a lot now experimentally, is that this sensory the caretaking from both parents. I talk a lot about mother, but doesn't need to become to come from. The mother can come from the father can come from other caretakers. It that's what's important for the developing infant to have that sensory exposure.
Nick Jikomes 1:14:19
Wow. So yeah, always having someone in the nest. Yeah, interesting. Interesting. Another thing I want to talk about that, you know, it sort of relates to this, but we're going into a bit of a different topic. Now, you study individual variability in in behavior and how that how that develops. And I haven't looked into this in too much detail, but I know that's a topic you study, and I know that you also seem to be studying it using a very peculiar animal. Can you talk a little bit about what you're doing
Marcelo Dietrich 1:14:51
there? Yeah, it's a little bit of a changing topic, but
I have always been fascinated. By this concept of individuality and then, and how we come about to be what we are
Unknown Speaker 1:15:07
and
Marcelo Dietrich 1:15:11
and, of course, there's a lot of debate out there about the nurture, nature. The importance nurture nature, nurture for development and then for this, for individuality, which means the genetic makeup of an animal and all the environmental experiences that they have. And I'm particularly interested in these concepts. In mammals, they have a complex brain. Have this postnatal period that they have a dependency on a caretaker. In that period, the brain is growing, the cortex is growing, and the baby is learning all this contingencies and being exposed to all the sensory experiences, it's quite unique to mammals. So I wanted to try to study that in a model that I can control the genetics and that I can control the environment. In other words, if I would have four Knicks in front of me, four monozygotic twins, clones that were raising the same conditions, would the four Nicks be interviewing me for the podcast, or maybe one would be sitting on my seat? Or what would happen? And would they have the same diseases or not? And I think that's important, because when we look at the data, for example, brain diseases, and we look at the human data of monozygotic twins, so twins that are genetically identical, usually we don't have 100% concordance. When is a disease, they have high concordance, which means if one sibling has the disease, the other will have in in brain diseases, the maximum you can get, it's really 80% but it's typically below 40% of concordance. There's a lot going on in the way the brain develops, in the way individuality develops. So how to study a complex mammal, control for genetics and control for the environment. So when you look at the mammalian Tree of Life on the 6500 mammals, there is one mammal that I grew up with them in this in the in Brazil, that they are madelu So the armadillos are the only mammals one particular species of armadillos, they always give birth to four clones always give birth to quadruplets. So it's such a fascinating experiment of evolution to create this striking animal has a brain, has a complex brain. It's a mammal, and it's a caretaker, and always generates four identical siblings. So you've
Nick Jikomes 1:18:13
got identical genetics as identical an environment as you're going to get and but nonetheless, you've got now four separate individuals, so
Marcelo Dietrich 1:18:21
you can have statistical power to look for how different they are or how similar they are. So that's one line of research that we are trying to do in the lab. I have very little to talk about it. Besides this conceptual framework, we are still,
Nick Jikomes 1:18:38
I would say, developing the system.
Marcelo Dietrich 1:18:41
Developing the system is very tricky. I have been working on that for like, a decade now, and now we have, we are, yeah, we are trying to generate the colony. We have 14 animals in my lab. So we are close to a point, an inflection point, that we will start having more to say. But
Nick Jikomes 1:19:00
in essence, what you're going to be studying is the neural basis of personality.
Marcelo Dietrich 1:19:05
Exactly one could say that way, yeah.
Nick Jikomes 1:19:10
And how much you know? Can you give us a sense for you know, how much natural variation do we see in laboratory animals like, you know, the inbred strains of mice that people normally use. Is there a fair amount of variability there.
Marcelo Dietrich 1:19:23
Yeah, that's a kind of say maybe there's a huge amount of variability.
So, yeah, I'm
so mouse models, rat models. Back in the day, they were taught that the best way to create these models as an experimental model system is to control their genetics. So you do sibling to sibling breeding. You breathe and breathe and breathe and breathe and breathe and breathe and breathe and so you create this inbreeding to a point that they are. I. Say, quasi genetically identical. So all the genes are the same, and they are all two copies of the same. So they are all homozygous, homozygote for those genes. So those are what we call the inbred mouse lines that we use the most classic using neuroscience, C 57 black six. So which means that animals has been bred for now 100 plus years in controlled conditions, and they they are fully homozygous when you try to do that kind of experiment. Actually, that kind of inbreeding, actually a minority of these inbreeding conditions will actually generate a line of animals that you can infect inbreed. Many of them become infertile because this the homozygotic. Being fully homozygous is really not a natural thing, yeah, yeah. So and the animals are never 100% identical, because there is always what we call a little bit of a drift in the order of one, yeah, but
Nick Jikomes 1:21:10
they're much more similar than two random people on the street would be.
Marcelo Dietrich 1:21:14
They are much more similar than two random people on the street. So the prediction was, if you do that in breathing, you have more constant genetic you decrease variability, yeah, in traits in general, including behavior and any trait, yeah, yeah. Size, body size, organ size, and surprising, that's not the case. You still have variability, even in this inbred mouse license, which is equally to the variability that you find. For example, if you take two strains and generates what we call an f1 so now it's heterozygous from two strains. Or if you take outbred strains, which are strains that are not genetically inbred. When you look at the the variability, for example, the percent that that trait varies compared to the mean of that population. Actually inbreeding does not decrease variability.
Unknown Speaker 1:22:18
Wow. Yeah,
Marcelo Dietrich 1:22:20
so there's a lot to talk about it, but one of the to me, one of the most remarkable experiments was done in Germany over a period of about 30 years, is studying traits of mice and showing that this variability persists despite being breeding.
And what, what was called,
back in the day, 40 years ago, was that's a third component. What is the third component is not the genetic genetically constant. You have animals raising semi identical environment, and the variability always remain. There's a chunk of variability that you can never suppress. That's a third component.
Nick Jikomes 1:23:10
I mean to me, to me what I think of here before I let you, let you take it away. But I had a conversation with a neurodegenesis named Kevin Mitchell at one point. And one of the things we talked about is just, I don't know what the official term is, but it's developmental stochasticity. There's just sort of a natural randomness in how many of the biological processes inside of us happen, such that, you know, even with identical genetics and identical cells, otherwise, sometimes things go in this direction and sometimes they go in that direction, exactly,
Marcelo Dietrich 1:23:41
yeah. Kevin is one of the, I would say, big thinkers on this field that stochastic developmental variability, the higher the complexity of the system. You have so many steps, you introduce some kind of random process, and you create a cascade the proper so you end up always with systems that are different, and that is certainly very important for the nervous system of a complex animal like mammals. So yeah, this scholastic field, so the stochastic developmental variability being the third component. So this component that cannot be controlled by genetics inbreeding, and cannot be controlled by environmental constancy or decreasing environmental gravity.
Nick Jikomes 1:24:28
And if we sort of put those things together. So you told us that, you know, we've created all these inbred mouse strains, they show comparable levels of variability across traits to non inbred strains. And so this would this would say that the developmental stochasticity is a very significant component of the variation that we see is a significant
Marcelo Dietrich 1:24:49
component, and is a critical component. And it's part also tells us that spark of the adaptive value. Now, of of the evolutionary context, it was a vote we evolved. Animals evolved to have that component as part of the variance, as part of the variant variability. As we know in evolutionary theory, you can only select for things that have variants. You need to you need to have variants to be able to select for certain traits. So it's striking to realize that actually there is a selection for the presence of variants as a default on the top of on the top of genetically identity, there's
Nick Jikomes 1:25:41
always variation for natural selection to work with, even in the absence of genetic variability.
Marcelo Dietrich 1:25:47
Exactly now, why would that be the case? Right? Because that's not being, for example, that if you I'm changing, if you generate for Marcellus and they are all genetically identical, they only do the natural selection evolution has to work is on my DNA. Yes, what is best? The structure of my brain is not going to necessarily pass today. Yes,
Nick Jikomes 1:26:19
yeah. Yeah. I mean, the difficulty here, conceptually, for me is, if we have four marcellos and they have some variation that's completely due to this developmental stochasticity thing, let's say two of them are adapted to their environment and two of them are not, they die off. Well, if the two of them that are adapted the environment such that they live long enough to reproduce their babies aren't now, like they're not necessarily going to actually inherit the traits that were adapted for you, because they're actually not encoded in the genes Exactly. So
Marcelo Dietrich 1:26:49
that's actually a puzzle. I don't think we have a good solution for that, and it's a puzzle in evolutionary theory. Why? For example, we have armadillos that give four oxpring Because why not, then generating four genetically different that at least you can select for those traits? And yeah, we don't, I don't think we have a solution to that discussion. One theory that any species they might have high rates of predation. So generating clones, you might have a higher chance of passing so you generate clones, you generate variation in behavior. They spread out in the environment. In the case of armadillos, they are solitary, so they can occupy a larger territory. They have high rate of predation. So the chance of one surviving is quite low. It's quite low. So you are actually never or very low probability having two of them surviving their offspring. So basically, you are multiplying the self you are you are spread, increasing the capacity of spreading your genes. Yeah. So that's one of the, I think the most accepted ideas behind that,
Nick Jikomes 1:28:07
and then, so what are some of the things that you guys are working on right now in the lab, especially on the maternal care side, and in the first part of our discussion, what are some of the upcoming questions you're trying to tackle, and where are things going to be going in terms of what comes out of your lab in the next couple years?
Marcelo Dietrich 1:28:24
Yeah, the we talk about this Armadillo world, I think this is going to be beyond couple years. And we talk a little bit about this unpublished work on adolescence and this realization that is feeding your hunger. Neurons are still being recruited for social behaviors during those sensitive periods of adolescence. So we, a part of my lab, is heavily invested in trying to understand at the circuit level what's happening there. So when the infant or another adolescence is alone. How is that information coming to the age of opinions to activate them? And is are those circuits different than the circuits that are involved in in the response to food or in the response to temperature? So can we understand more about that, and would that give us insight of what's actually happening there? So part of my lab is trying to understand that, and another big part of my lab is trying to understand, how does the infant make this concept of a caretaker? So how is a caretaker, one would say, encoded at the level of the brain? Where is that information and and then, how does that information is used for future social behaviors? Hmm, in other words, this, this, this primary social relationship of the infant with the caretaker is that, is that relationship at the nearest circuit level being useful? And how come? How so for future social relationships that have distinct characteristics. An adolescent that's playing is a very different social behavior compared to an infant that's calling attention of a caretaker, and an adult that's engaging sexual behavior, territorial behavior or other kind of behavior is still another kind of social relationship. Are the social behaviors of different periods of life, uh, somewhat related to those early relationships with the caretaker? Yeah, and, and how? So, you know. So we are really going to that direction at the neurosciric with neuro neurocoding level, yeah,
Nick Jikomes 1:31:04
yeah. I mean, it's very natural to think that there's going to be significant findings there. Because, you know, I'm thinking of the the Okinawa movie you told us about, you know, someone, if you're growing up in a situation where someone's always in the nest, you always have a loving caretaker, you're probably going to have a very different propensity to develop certain behavioral tendencies, certain disease tendencies or disorder tendencies, compared to if you grow up an environment where people are absent more often, or someone aggressive is around, etc, etc,
Marcelo Dietrich 1:31:31
absolutely. So there's at least two ways to broadly think about this. One is that the relationship, the calming effects or the healthy relationship, affects, in some ways, how other systems in the body develop enhance the long term effect of their relationship is by leaving these marks okay. And the other way to think is that at narrow encoding, for example, their relationship with the mother is encoded as somehow in an emotional sense, in the neuro coding sense, and then later in life, when the animal is subject to some events in life, You will use that information as a template, as a template, yeah, and I think that's important for social behaviors, yeah, it reminds
Nick Jikomes 1:32:27
me a lot about the basic way that people who study songbird study vocal learning. There's a critical period in which a template develops and crystallizes, sort of every subsequent learning event is in many ways compared to that initial template,
Marcelo Dietrich 1:32:41
yeah, absolutely. There are some experiments that are quite mind blowing. They were done in the late 60s, second half of 60s, 1960s based. They raised, they raised mice with rats. So they took mouse babies and they gave to rat mothers, and those mouse babies raised by rat mothers, when they become adults, later in life, they will choose to socialize with rats, not with mice. So the idea being that there are inborn tendencies for social animals to socialize, yeah, however, the experience of what king of what, what a social, what a social object is, is actually learned,
Nick Jikomes 1:33:41
yeah, yeah.
Marcelo Dietrich 1:33:42
He's learned during sensitive years of life, and then the mouth seems to be during lactation.
Nick Jikomes 1:33:48
There's, there's so many, there's so many fun YouTube videos out there where people say things like, my cat thinks it's a dog, or things like that. You see the cat running around with the dogs instead of the cats or whatever.
Marcelo Dietrich 1:34:00
Yeah. So anyways, those are kind of things that we are trying to study at the at the nearest circuit base and the nearing base. Yeah.
Nick Jikomes 1:34:09
Well, this has been fascinating. I really like the spectrum of work that your lab does. It's really cool stuff. Are there any final thoughts you want to leave people with? Anything you want to reiterate either about your scientific work and the things that we talked about, or maybe even how your work has influenced how you think about, you know, social relationships and how we relate to each other as humans. Yeah,
Marcelo Dietrich 1:34:32
we start with the sentence of Harlow that we have to learn how to love before we learn how to live. And I think, yeah, I have had my lab since 2014 so 10 years now. And I think working on this field and doing some of these experiments that we do really brought that concept close to heart.
And, uh. Um,
I think, you know, if we look at things, for example, the NIH budget, which is the largest entity of funding in the world, I think the NIH budget to Alzheimer's disease year tag is such a fundamental problem, is about $6 billion a year. Year tagged, I believe, the NIH budget for the National Institute of Child Development, which means the entire research that the country does in child health and child development, including clinical trials. Everything included, I think, is under $2 billion so I think if I would leave a message is that development is very critical for health in January, understand an infant is not a mini adult. An infant is a complex, dynamic system that is solving physiological problems than in anticipating for the future ones. And this machine is beautifully working and orchestrated. And whatever we do, as you said, Change diet or early life stress or it will change how the systems develop. But that's a very fundamental problem to work. And it will be amazing to have more people join in the forces. And, you know, thinking about these problems together is in a is a fascinating moment of science. I tell always my group. You know, it's just mind blowing the tools that we have and the the depth of the questions that we can ask, it will be amazing to have a vibrant community in that regard.
Nick Jikomes 1:36:51
All right. Well, Professor. Marcelo Dietrich, thank you very much for your time. Fascinating stuff, and I hope to talk to you again at some
Marcelo Dietrich 1:36:57
point. Thank you, Nick.
Was a pleasure.
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