Podcast: SciCafe—Science of Love with Bianca Jones Marlin

BIANCA JONES MARLIN (Neuroscientist and Postdoctoral Researcher, Columbia University): Thank you. Thank you. I'd like to thank the Museum of Natural History for having me tonight, and thank you all for coming out in the rain to hear a little bit about love. Hopefully you'll find it interesting. I know it's around Valentine's Day so you're interested in talking about love with your partner. But I'm going to talk about babies.

My research aims to bridge the gap between nature and nurture. Things that are innate, things that we are born with, versus things that were learned, and what biology gives us versus the way we can adapt to biology and how we can learn and adapt in an environment.

Why is this essential? It's essential for our survival. And not just our survival as individuals but the survival of our lineage, of our genetics, usually through our offspring.

How do we take the world in? We take the world in through our senses. And so, let's take a step back and see how the senses will lead to changes in our offspring. I'll set the mood.

We're here tonight at the Museum of Natural History. You're drinking your red wine, seeing it glisten off of your partner's face. He whispers over to your ear and says, "I like your shoes." You smell her perfume. And these senses that are coming in—the touch, the hear, the smell—they put you in a type of mood, and the mood sets the dynamic between you and the person.

And that mood eventually sets the status with the person. Sometimes statuses come about in this manner, but that status will eventually set a different type of mood, and that's the mood of motherhood.

I study how mothers interact with their offspring for their offspring's survival.

When a mother first gives birth, the smell of her baby's head, the feeling of its velvety skin and the sounds that it emits set the mother in a particular type of mood.

Babies have a limited ability to interact with their caregivers. They can do one of a few things to let you know, us as caregivers know, how they're feeling. One example is here.

[RECORDING OF YOUNG CHILDREN LAUGHING]

MARLIN: So, you know that baby's enjoying her time. And another way babies communicate is through this:

[RECORDING OF BABY CRYING]

MARLIN: I hope you're asking yourself, Who would record this poor baby crying instead of going to pick them up? That's my daughter.

In the same manner that offspring make cues that we as caregivers take care of them, mice do the same thing. Mice are my model organism that I use to study how brains change.

These are the mice babies that I use. They're called mouse pups. Yeah, they're super cute. And when they get cold, they emit something called an ultrasonic vocalization, and that's shown here. It's plotted frequency over time. Are there any musicians in the room? Would you like to sing this? You can't. It's ultrasonic, which means it's above our hearing range, so you can't really hear it.

But it's plotted frequency over time, so if I were to sing it downgraded, it would be like:

[MARLIN MAKES COOING NOISE]

MARLIN: And those sounds alert the mom, so when she's in the nest and if pup gets out of the nest, she'll orient toward the pup, she'll pick it up and she'll bring it back to the nest. I'll show you an example of that here.

Virgin females, however—animals that have never given birth to a pup—won't perform this task. They'll ignore the pup, and sometimes they'll cannibalize the pup. I'm not going to show you that.

And herein lies the question: How does an existing social cue—the sound of a baby crying—that is consistent between both groups gain relevance after an experience? And this experience is the experience of motherhood.

We had a candidate neuromodulator, a candidate chemical that we wanted to check out, and that was the love drug, oxytocin. Oxytocin's released from a part of the brain called the paraventricular nucleus of the hypothalamus. If everyone can take their left hand and put it on their nose and their right hand and put it right on top of their ear—this is a great picture—where the two fingers meet, that's where your paraventricular nucleus of the hypothalamus that projects to the pituitary gland is. That's where your oxytocin's released. That's where the magic happens.

In mice, who also have a paraventricular nucleus of their hypothalamus, oxytocin's released and can get through the body.

It's released through a myriad of ways. During sex, it's released during orgasms. It's shown to increase trust and generosity. It's also important for pair bonding.

Here's an example of a vole, and the way oxytocin operates in the brain of a vole is very intriguing. There are two species of vole: prairie voles and Montane voles. Here's an example of a prairie vole. They're monogamous, so after they find a mate, the male decides to stay with the female and they raise children together.

The Montane voles, however, they're polygamous, so they go from female to female, and they don't stay with their litter. What's interesting here is their brains respond to oxytocin differently, which makes it such a candidate molecule for us to study.

Oxytocin is also essential for the birthing process. If anyone's ever been induced, they give the correlate, which is pitocin, in the hospital to induce birth. It causes uterine contractions and it causes milk letdown, so it's essential for breastfeeding and continually released during breastfeeding for pair bonding.

It's also released during touch and eye contact and prolonged hugs.

Given such a beautiful molecule, I found it really interesting when I was looking up information when I first started this project that showed that the hype about oxytocin is dumb and dangerous. Ed Yong, who is a very prominent neuroscience writer, called it oxytocin-schmoxytocin and said it was over-rated.

I also found you can find it on Amazon. Don't find it on Amazon. It's not really oxytocin.

But I was a little bit perturbed going into this question, wanting to use oxytocin as a target molecule but realizing that there's not much work done on how oxytocin really works. So, I decided to address the hard science of oxytocin. Spoiler alert: This article that came out in Nature was written about our work that we did on oxytocin.

And so, today I'm going to talk to you about three things that oxytocin does, where it works in the brain, on what time scale in mice, and how it actually changes the brain to make sub-par caregivers better caregivers.

First, let's check out where. I hypothesized that it would be in the hearing centers of the brain, given that when a baby cries, the mother's first reaction is to orient towards the pup, so maybe the hearing centers of the brain, called the primary auditory cortex, were really important in this discovery.

Here's an example of the auditory cortex here, circled in the hearing area of the schematic of the brain. In the brain, we have neurons, and these neurons respond to different molecules. Oxytocin, for example. Caffeine. THC. Oxytocin is also not OxyContin. It's different. I'm going to point that out.

And so, these neurons in the brain respond and fire when certain drugs hit them. How does that happen? It happens because each neuron has a specific receptor on it. The receptors take the molecule, attach it to the neuron, and that allows the neuron to fire, to propagate and to have a conversation with the other neurons in their milieu.

Because we were able to dabble with the oxytocin receptor, what we did is we made all the cells red. This is to show you the next slide. Before we were able to make the cells red, we couldn't find an oxytocin receptor. We couldn't find an oxytocin receptor antibody, which means I can use a drug to add it to the oxytocin receptor, and it will turn the cell red.

So, we didn't know where oxytocin was, so we created a novel antibody shown here on this slide. Each one of the cells—the dots here are cells, neurons. These are real neurons in the brain. Well, out of the brain because I took a picture of them. They're stained with red, which means they're oxytocin receptive.

What we saw, which was really surprising, was that there are more oxytocin receptors in the left side of the brain than the right side of the brain when it came to the auditory cortex. Why we were so excited about this is because it was the first opportunity to show lateralization to auditory cortex.

Why is this exciting? Because in humans, we have lateralization. The Broca/Wernicke area is usually found on the left side of right-handed people, and that's an area for communication. So, we may have found a locus for communication, given that oxytocin is on the left auditory cortex more than the right.

We also looked at different types of cells in the auditory cortex. They are excitatory cells and inhibitory cells, and I would think of it like this: Excitatory cells are like the kids in the front of the bus that are making a whole lot of noise and they're really excited, and then—oh, I guess in the back of the bus they make noise. I haven't taken the bus in a long time.

The kids in the back of the bus make a lot of noise, and the nuns in the front of the bus—I also went to Catholic school—the nuns in the front of the bus are telling everyone to quiet down, and those are the inhibitory cells.

So, you have the people that are making the noise and the people that are telling other people to quiet down, and that's how balancing happens in the brain.

We showed that there are oxytocin receptors on both the loud cells and also the quieting cells. The loud cells are in green, and the quiet cells are in red. Oxytocin can both make things spike more or spike less, which means it has a lot of control in the brain.

When does it work? I did an experiment where I have a pup in a chamber. The pup is shown here, the little green pup. I put a virgin animal that's not cannibalizing but will ignore the pup, and I wanted to—a lot of screening went through that experiment. And I wanted to see how the virgin would interact with the pup.

When she didn't pick it up—which she normally didn't—I then treated her with oxytocin. I did it through something called an intraperitoneal injection, which means I'm injecting it into her body. I also used something called optogenetics, "opto" meaning "light," "genetics" meaning "changing the genetics."

What optogenetics does is we have an animal that allows neurons to fire when we shine light in the brain. We genetically modified it so that every time we shine light, the neurons fire, so I'm releasing endogenous oxytocin, oxytocin from the animal's own body, and using that to see the behavior.

I then put her in the chamber with the mom after she had the flood of oxytocin so she can see how a real caregiver does it, and she can sit back and learn.

Here's an example of a video in which we have the blue light shining in the brain—you'll see a fiber and a blue light shining in the brain—and this animal that originally was not retrieving at all is all of a sudden retrieving very well, based on the release of oxytocin.

When we illuminated the left auditory cortex, we were able to get this behavior. Just shining light in the left auditory cortex, the left hearing center, allowed for an animal to become a better caregiver.

Oxytocin makes bad babysitters into great nannies.

We then wanted to know how does this work. What's changing in the brain to allow for a behavioral change? In order to check that out, I did something called whole-cell in vivo physiology. It's a whole mouthful, and it's actually a really hard technique, but I'm going to walk you guys through it, so by the end you'll be whole-cell in vivo physiologists.

What I do is I have an animal who's anesthetized. She's usually on a ketamine drip, in all truth. We've given ketamine so she's not feeling any pain, but she can also still hear. We play the pup call, and I record from a neuron in the brain to look at spiking activity to see how the neuron's talking to its immediate neighbors.

How do you record from a very small—very small, 10 to 20 microns, very small—neuron in the brain? I take a glass pipette, pretty much like a glass straw, I heat it over a fire and I pull it until the opening is about less than 10 microns, maybe in the order of five microns.

And then I do something really, really sophisticated: I take a tube, I stick it on the other end of that pulled straw, and I take that part and I put it to my mouth, and then what I do is I kiss it while it's in the brain until I find a cell and suck the cell onto the tip. That's whole-cell in vivo physiology.

And once I'm able to kiss onto the cell so I can record from a single cell in the brain, I can see spiking activity. Because neurons are electrical and that's how they communicate with their neighbors.

I'm going to show you a few traces that I actually recorded from single neurons in alive animals.

And as you can see here, there are three spikes that every time I play the pup call in a mother—this is an anesthetized mother—we see a spike that happens at the same time. That means that neuron is encoding a message. Every one of these lines is a different time I play that call, and every time the neuron's firing at the same exact time. It's trying to tell their other neighbors something.

However, in a virgin animal, this is a different call because I use a call that makes the best response. In a naïve animal, we see spiking, but there's nothing that's time locked. There's nothing that's actually encoding a message. It's kind of just making noise.

However, after a virgin learns to retrieve just in the auditory neurons in the brain, we start to see that time-locked response. That neuron's firing and encoding a message.

And so, I wanted to ask, How am I making a virgin's brain into a mother's brain by adding oxytocin? And because of whole-cell physiology, we're able to answer that question.

I attached onto a cell in a virgin mouse. I played the pup call, and I looked at the spikes that her neurons told me. I then illuminated the area that I was recording from to release oxytocin endogenously, so I'm using its own oxytocin from its own body in the area I'm recording from while playing the pup call.

What we start to see is that the neuron starts to fire a lot more. There's an increase in its excitability. And after about three hours of recording from the cell, we start to see this time-locked response. We saw in real time how the brain changed from an inexperienced caregiver to an experienced caregiver just in the hearing parts of the brain.

And so, I answered, Where is this happening? In the auditory areas. When is it happening? Very quickly. And how? By changing the way the neurons fire in the brain to change the response to the pup call.

Finally, now if you search "oxytocin" on Google, you will get a lot less of, "It's trash," and "Oxytocin-schmoxytocin" because this study actually picked up a lot of good press, which is really exciting for us as scientists to be able to illuminate some area that's unknown prior and give some information to the bigger scientific community. It was covered in National Geographic, in Science magazine, and also it got to the top 100 stories of 2015—thank you—further giving information for how oxytocin works.

And so, we looked at the natural oxytocin in the brain, but how the experience of hanging out with a good mom actually makes it better. We looked at how something that's innate, like giving birth, having a flood of oxytocin and then being able to take care of your child works, but also, it can be learned when given oxytocin. So, there's a component that's innate and also a component that can be learned. Something that biology gave us, but also something that you can adapt to, further building that bridge. And that bridge is for the survival of their offspring.

But when we take a step back and look at how oxytocin and mice can play a role in humanity, I think it's really important to understand that mice have a certain level at which they want to propagate their offspring, but we saw that virgins took care of pups that weren't their own. I think that's really important because it's not necessarily the propagation of your offspring, but it's the propagation of their species. I think that really applies to us as humans as well.

Some of the work that motivates the science that I do comes from these statistics. Four out of seven children die a day from child neglect and abuse. The average life expectancy is 20 years shorter. The brains of neglected children have less white and grey matter. When I read this number, I just cringe because the financial impact is enough to send one child to college, and we all know how much college costs.

And so, these studies I think are really important. But moreover, the reason why I think I'm so motivated to study how parental experiences and how supporting parents and supporting offspring better supports humanity is because of these two people and this precious child.

These are my parents, and that's me. My parents have taught me a lot in life, but one of the most important things that motivates my science is that they are my biological parents, but they were foster parents. I grew up with foster brothers and sisters who came from other homes in which they weren't honored, in which they were not treated well, and whose parents had a hard time taking care of them.

And so, to grow up in an environment where my parents were able to take care of children that weren't their own, children who came from different environments, and still see people live and thrive and learn really motivates the studies I do.

Right now at Columbia University in Richard Axel's lab, I'm studying transgenerational epigenetic inheritance, so how much trauma that your parent had can be passed down to you through sperm and age, and how to potentially understand that and maybe modify and stop that from being passed on to future generations. Thank you.

[APPLAUSE]

MODERATOR: Yes. Time for questions. Any questions? Oh, I have one over here.

AUDIENCE QUESTION: Okay. Thank you so much for your enlightening talk.

MARLIN: I would love to see where you are. Okay.

AUDIENCE QUESTION: I know that the reason we're having this subject is because Valentine's Day is basically in a week. So, let me ask a very practical question. Let's say my girlfriend was less than affectionate—

MARLIN: Don't buy it on Amazon.

AUDIENCE QUESTION: Could I slip some oxytocin into her cocktail?

MARLIN: Oxytocin is not very stable when you buy it on Amazon or Google. You have to get it from hospital-grade, etc. But why buy oxytocin when you can release endogenous oxytocin? So, hug her. Look into her eyes. Love her a little.

[APPLAUSE]

AUDIENCE QUESTION: I had a question about the portion where you said some of the behavior was learned. What would happen if you modified virgins without them seeing the behavior, and did mothers ever learn from anyone?  

MARLIN: Excellent questions. We had two cohorts. We had one cohort that was co-housed, which means they lived with the mom and the pups, and another group who was not co-housed, but they both got oxytocin. And we had a third group that was not co-housed without oxytocin, so a control group.

What we saw is that oxytocin accelerates the learning of retrieval behavior a lot. Why do we say "learning"? Because if the animal gets saline but live with the group—so, saline as a control, which is just salt water, and they still live in a group—they learn, but they learn maybe a few days later. The animals with oxytocin learn within six to 12 hours. Saline animals learn within 12 to 48 hours. Animals with oxytocin but not living and watching the parent learn in the span of three days. And the animals without oxytocin or anything and not living with the parents usually don't learn. If they do learn, it's after a week. And so if you think about it evolutionarily, if you wait a week to pick up your child...

And so, oxytocin plus the observation is a learned component. Thank you for asking that question.

AUDIENCE QUESTION: Hi. How much of an influence does oxytocin have on the paternal parent?

MARLIN: Ah, also an excellent question. Oxytocin, the receptor, I showed you the receptor. It looks similar to another receptor called vasopressin, and males have more vasopressin. Sometimes oxytocin will also bind to that receptor, but with that being said, males have oxytocin receptors, females have oxytocin receptors whether or not you're a mother. Mothers versus non-mothers all have the same amount of oxytocin receptors, so it's almost as if nature has primed a female if she chooses to give birth, the oxytocin receptors are set up there.

Males do have fewer oxytocin receptors, but they still have them. And when we treated the male mice with oxytocin, the ones treated with oxytocin did learn at a faster rate, but it was on the order of about three days, compared to the six to 12 hours.

My husband's in the room, so I can only say so much about that.

AUDIENCE QUESTION: Okay, I'm hitting on one of the very last things you said, which is the idea of trauma being passed down. I've read studies of that. We're not talking about infants. Most of those studies have been done on sentient children. How can you differentiate nature versus nurture?

MARLIN: Excellent question, and this is why I choose to use the model organism mice. I use the human studies to get information from where I should be focusing my research, but with mice, we can take a new pup, separate it from its parents and have it fostered by another mother that's lactating. Or we can do in vitro fertilization, so we can take the actual sperm out of the mouse, put it into another female, and the mom or the kids have never experienced the father.

So, we can actually take that nature versus nurture component, and I don't want to push the fact that they're two separate things. I really do think that they work together, and that's why I would like this research to build a bridge. They work in parallel. So, the nature is the environment, the nurture is also the environment. The nature are the genetics, but the nurture is also part of the genetics.

And so in this manner, I'm able to separate them so I can look at both the nature and nurture components separate from the father.

AUDIENCE QUESTION: [inaudible].

MARLIN: It's not the same. It's called epigenetics, and "epigenetics" means "above" or "around" the genome. Your genome doesn't change. Outside of random mutations, it does not change. But epigenetics allows certain parts of the genome to be read or not read, and that means it will turn into a separate protein, which may change a separate part of your brain, which may change behavior eventually. They're markers that change around the genome. And so, those are the things that we're looking at.

AUDIENCE QUESTION: Hi. Great presentation.

MARLIN: Thank you.

AUDIENCE QUESTION: My question is I heard from someone that doctors are now experimenting giving the oxytocin drug to children on the autism spectrum. Do you have any knowledge of that, first? And second of all, does it actually work in terms of dealing with social withdrawal symptoms?

MARLIN: Yes, studies have been done on people on the autism spectrum with oxytocin. What research has shown in humans is that intranasal oxytocin, still in a controlled model, sprayed up the nose will actually go through into the brain and also cause natural oxytocin to be released. And what it does, it seems to increase certain things like eye contact, and it's able to differentiate sad faces versus happy faces in those individuals who have taken the oxytocin who are on the autism spectrum.

Prior to that, it seems that it's a difficult thing for people on the spectrum to do, maybe tell who is happy with them and sad with them based on facial recognition. And also making eye contact. So, those things have been shown to be increased when oxytocin's present.

And so now the question is, How is oxytocin working in the brain to allow these things to happen? And that goes back to what we're doing here, being able to record from neurons and see how it changes neurons so we can see how it changes people.

AUDIENCE QUESTION: I was wondering if any of the mice that you were working with didn't produce any oxytocin at all.

MARLIN: Yeah, we can genetically cause animals not to produce oxytocin. It's called the oxytocin knockout mouse. We wanted to dabble with those, but the problem with those is they just cannibalize. They are not good with—they can't give birth. Sometimes when they do possibly give birth, it's not—it's really hard to work with those animals.

So, what we did instead is that we used a drug to silence the oxytocin working in the auditory cortex, so we were able to stop oxytocin from working there, and we saw a decrease in behavior. We wanted to maintain endogenous oxytocin as a control because if not, stuff gets really bad.

AUDIENCE QUESTION: [Inaudible].

MARLIN: The question was asked, Is it a defect that possibly happens? We see the receptors there. It's hard to tell whether or not oxytocin's always there, and so it's a good question to dive into in the future. But all the mice that we did use seemed to have endogenous oxytocin in the receptor that's present. I wonder if it was active at the proper time. That was my question.

AUDIENCE QUESTION: [inaudible].

MARLIN: The question is, If they don't produce it, can we add it in? I think it's the hope in the future. If there are people who have in some way produced less oxytocin, could we supplement that? Very good question.

AUDIENCE QUESTION: Hi. First I want to thank you for such a wonderful presentation.

MARLIN: Thank you.

AUDIENCE QUESTION: You were phenomenal. We really learned a lot.

MARLIN: Thank you.

AUDIENCE QUESTION: I was just wondering, the mice who were given the—the virgin mice who were given the oxytocin, let's say weeks down the road, did they still retain that maternal instinct?

MARLIN: Excellent question. That's a very good question. What we did is we did exactly that. We tested animals 30 days and 60 days later. What we observed was that the animals who were initially retrieving, after they learned the retrieval behavior, maintained the retrieval behavior. And what that shows is oxytocin is necessary for the induction of the behavior but not for the maintenance of the behavior. It's essential to learn the behavior, but it doesn't need to be present every time the animal retrieves. Great question.

AUDIENCE QUESTION: Hi. I have two very brief questions. One, have you looked at post-partum depression and the result of oxytocin? That's one. And two, are there other substances like CBD or THC that would also release oxytocin?

MARLIN: Ah. The latter question, I currently don't know the answer to. I wonder what other areas in the brain project to oxytocinergic areas that release oxytocin. Because it would have to be neurons that have the THC receptor that then talk to oxytocin and then talk to other areas of the brain.

For the first question, I hope that's where this study helps to bolster. We haven't studied it in humans, but it's definitely something that's talked about in the field, how oxytocin can aide in maternal bonding and that within itself can aide in maternal post-partum depression. Excellent question.

With every study that we do in humans, it's essential to have some type of background in bench research, we call it, with mice. And so, I think this is where this data is really important.

AUDIENCE QUESTION: I had one question, actually. Do the babies as well release oxytocin when you do that?

MARLIN: I don't study that personally, but other research has shown that oxytocin is also released in the pups when they suckle. And also, they're getting oxytocin from the mom. But I personally haven't studied that.

MODERATOR: That's all the time we've got for tonight, so please join me in thanking Bianca Jones Marlin.

MARLIN: Thank you. Thank you.