In friendships, in romance, in the songs we listen to, books we read, and movies we see. So whether you love love, hate love, or are somewhere in between, you’re still hearing about it all the time. And that means you’ve probably learned about a molecule called oxytocin, aka the ‘love hormone’ or ‘love drug.’
Oxytocin was at first considered a hormone strictly for childbirth and nursing. But, starting around 50 years ago, research began to shed light on the vastness of its importance, in part with the help of cute little animals called prairie voles, one of very few species in the animal kingdom who form monogamous bonds.
In this episode, Sam and Deboki unpack what we've learned oxytocin can and can't do, why you can't reduce love down to a single molecule, what happens when we not only fall in love but stay in love, and how our brains adapt to the loss of a loved one.
Transcript of this Episode
Sam Jones: Ah, love. It’s the subject of so many songs, books and movies. So whether you love love, hate love, or are somewhere in between, you’re still hearing about it all the time. And that means you’ve probably heard about a molecule called oxytocin, aka the ‘love hormone’ or ‘love drug.’
Welcome to Tiny Matter and happy almost Valentine’s Day! I’m Sam Jones and I’m joined by my co-host Deboki Chakravarti. I’ll admit it’s a little corny to do an episode about love this time of year, but I think the science behind these intense connections we share with each other is fascinating. In truth, I’m not really a Valentine’s Day person, never have been, minus the chocolate of course. What about you Deboki?
Deboki Chakravarti: Same, I’m just here for the chocolate. But even away from the holiday, love is a nice thing to have in our lives. So in today’s Tiny Matters we’re going to break down some pretty interesting history surrounding that ‘love hormone’ oxytocin.
And we’re going to learn about the important role that cute little animals called prairie voles have played in helping us understand how humans form and maintain bonds, and how we process loss. Plus we will get into a mix of fascinating work which will make it clear that, as researcher Daniel Quintana put it:
Daniel Quintana: You can't reduce love down to a single molecule.
Sam: Yep. Oxytocin is one piece of the very complex love puzzle. But it’s still an important piece. So let’s start there.
Daniel Quintana: Oxytocin is a hormone which is mainly produced in a small structure of the brain called the hypothalamus. So if you were to curl your tongue back inside your mouth as far back as you can go, you would almost be touching your hypothalamus. It’s at the base of your brain, it’s round, about the size of a pea.
Sam: That’s Daniel Quintana again. He’s an associate professor of psychology at the University of Oslo. Oxytocin is not only in your brain, your pituitary gland also secretes it into your bloodstream, which means that it has a much broader impact on your body. And it has a fascinating history.
Daniel Quintana: It was discovered about a century ago for its role in childbirth and in breastfeeding, but back then it wasn't known as oxytocin. Back then, researchers would take a small extract or a bit of fluid from a gland which sits at the base of your brain, called the pituitary gland, and they would find out that this actually has an influence on how the uterus contracts — therefore having a role within childbirth.
Sam: Not long after, researchers discovered that oxytocin is really important for breastfeeding because it helps with the release of milk. In 1955, scientist Vincent du Vigneaud won a Nobel Prize, in part for isolating and artificially producing oxytocin, marking the first time ever that a polypeptide hormone was synthesized. And for a very long time, oxytocin was seen as strictly a maternal hormone.
Daniel Quintana: And it wasn't until the eighties that researchers actually found, well, it's more than maternal physiology. Oxytocin also seems to play a role in bonding between the mother and the child. But this research was done in goats and sheep and they have quite an extraordinary pair bond. A mother can identify its offspring very easily within an entire flock. And oxytocin plays a really important role in forming this bond. This research started going along and more and more there was this link, although researchers actually found concentrations of oxytocin in males, they were at a loss.
They're like, “well, males have oxytocin, but we don't really know what it does. At the moment, we just see it as a maternal hormone.” But then things really started to kick off in the eighties and the nineties when researchers began looking at this little critter called the prairie vole.
Zoe Donaldson: This gets a lot of attention around Valentine's Day, and so that's why, amongst the vole community, we often call it Volentine’s Day.
Sam with Zoe Donaldson: <laughs> I love that.
Deboki: That’s neuroscientist Zoe Donaldson, who is an associate professor at the University of Colorado Boulder. Prairie voles are rodents native to the midwest United States. They’re around 5 inches long — an inch or 2 longer than your average house mouse — and they live for about a year and a half.
These animals are unique within the animal kingdom because they are socially monogamous, which only around 3-5% of mammals are.
Zoe Donaldson: Prairie voles are very different from mice and rats. A mouse and a rat, they meet another mouse or rat, and if there's a mating opportunity, that's fantastic, but then they go off and they leave. The females raise the offspring on their own, and this is dramatically different from prairie voles. For prairie voles, when they meet in the wild, they'll establish a burrow together and then mom and dad will take care of the offspring and that mom and that dad will often have successive litters.
Sam: About 50 years ago, it was field ecologists who first discovered that prairie voles aren’t your average rodent. They were out trapping and releasing critters to answer questions about population density and species movement in that area. And when they looked in the traps, they tended to find two prairie voles there together. And not just that — they would let the voles go and then find the same two voles in another trap. Which I think is so cute…
Deboki: It’s like the epitome of a codependent relationship but in a really cute way
Sam: In a less toxic way we hope, we don’t know.
Zoe Donaldson: And so a field ecologist went and talked to one of his colleagues, Sue Carter, who is a behavioral neuroendocrinologist, and that's sort of the origin story of prairie voles, because she was studying all kinds of hormones that are involved in social behavior in other species like hamsters, for instance.
Sam: With the help of prairie voles, scientists were able to find a role for different hormones and neurotransmitters in pair bonding. These are molecules like oxytocin, vasopressin, and dopamine, which is a well known molecule in our pleasure and reward system, which we’ve talked about a bit in past episodes.
Deboki: So prairie vole research started to take off, and scientists were finding that increasing oxytocin levels in their brains could accelerate their pair bonding. Conversely, decreasing oxytocin levels negatively impacted prairie vole pair bonding. Enter: the love hormone.
Daniel Quintana: It was really around the nineties a bunch of new stories came out describing this research. “Look at these little animals they pair for life. Isn't that cute? And it's probably the same for humans.” Here we have the love hormone. In terms of the human research, there was a really big study in 2005 which found that oxytocin increases trusting behaviors in humans — what was reported as a pro-social effect between humans. And this is what really put oxytocin on the map. I do think it's important to say that this particular study, they attempted to replicate this and it wasn't entirely successful, but regardless, this 2005 study in humans was what really got things started.
Sam with Daniel Quintana: In terms of what we know about the impact of oxytocin on humans forming bonds, forming relationships, where are we at with that?
Daniel Quintana: We can't experimentally knock out the oxytocin system in humans. What we can do is increase oxytocin levels in humans. And the way that we do that is through intranasal administration. By intranasally administering oxytocin, we can increase levels of oxytocin within the central nervous system.
Deboki: In one study, researchers found that, when given the oxytocin nasal spray, heterosexual men find their partners to be more attractive than female strangers, compared to males given a placebo spray.
Another experiment found that partnered heterosexual men given oxytocin nasal spray stood four to six inches farther away from an attractive woman they didn't know, compared to men who were given a placebo.
Daniel Quintana: So the argument here was that oxytocin strengthens the pair bond for relationships. So there's been a lot of studies in that regard, but again, I think it's really important that these studies be replicated, and they haven’t necessarily been replicated at a large scale. On top of that, there's been a lot of work looking at oxytocin concentration. So we can measure oxytocin, either blood or saliva, and people have looked at the strength of pair bonding and at least reported that within the early stages of a relationship, oxytocin levels are increased, suggesting that it may play an important role in pair bonding.
Deboki: In addition to needing larger studies to really understand pair bonding, those studies also need to be more diverse. For instance, we need more data on women.
Daniel Quintana: Which is kind of funny, considering that oxytocin was first considered a female hormone. And this I think is a real shame, and we're losing a lot of potential knowledge and information this way. One thing we're trying to do in our own lab is including females in our research to actually understand what's happening here. And I think a lot of the reason that people have not included females in their research is like, “oh, well, the fluctuation of progesterone, estrogen across the menstrual cycle makes it really difficult.”
Deboki: If we don’t understand how oxytocin’s role changes throughout a menstrual cycle or in the context of other chemical changes throughout the body, we’re not getting the full picture.
Sam: OK, so. Decades of research has made it clear that, at the very least in prairie voles, oxytocin is key to pair bonding. But that research was pharmacological, meaning the animals were given drugs that either led to more oxytocin in their system or stopped it from interacting with its receptor on cells, blocking its activity.
Dev Manoli decided to take a different approach — a genetic approach.
Dev Manoli: Love is a simple word that means a really complex thing, and attachment and bonding is exactly the same way — slightly bigger word, equally complex thing. In the same way that the brain is really complicated, so are the genetics of something as complex as attachment.
Deboki: Dev, who is an assistant professor in the Department of Psychiatry and Behavioral Sciences at the University of California San Francisco, is a child psychiatrist and neuroscientist whose lab focuses on how we form social attachments and the role of both genetics and experience.
He and his lab figured out how to edit the genome of a vole embryo using CRISPR, a groundbreaking gene editing technology that really deserves its own episode. But what you need to know for today is that Dev and his lab used it to get rid of the gene that codes for the oxytocin receptor that’s produced on cells. Without its receptor, oxytocin can’t bind to cells, meaning these animals are born without oxytocin signaling.
Dev Manoli: So the experiment that we first did was we took an animal that either had or didn't have the oxytocin receptor — male or female — and we put her or him with an opposite sex partner who is wild type. And we just put them together for a week. And many studies have shown that that's enough time for two wild type animals to really, really form a tight pair bond.
Sam: And at the end of the week, much to their surprise, they found that these animals without oxytocin signaling were still pair bonding to their wild type partners.
Dev Manoli: They wanted to spend time with their partner and didn’t necessarily want to spend time with a stranger. And they showed very similar behaviors. They huddled with their partner, they interacted them in a very prosocial way, which was initially a surprise because what had been shown was that when you disrupt oxytocin receptor signaling in a wild type animal, when they're in that period of what we call cohabitation, that prevents the formation of pair bonding.
So somehow genetically these animals are in some way, shape or form compensating for the absence of oxytocin receptors both to form and display a partner preference. Which, if you think about it, isn't surprising. These are fundamental aspects of how animals reproduce.
Sam: Dev’s work showed that oxytocin isn’t the only molecule involved in that critical period where pairs form. As Dev put it, it wouldn't make sense from a genetic perspective for there to be a single point of failure disrupting an entire very important system.
Zoe Donaldson: It essentially says that these systems are so robust and so important from a biological perspective that these animals have ways to form bonds even in the absence of oxytocin signaling within the brain.
Sam: That’s Zoe Donaldson again.
Zoe Donaldson: And to me, that's crazy, but it also opens up these huge possibilities because we're already seeing at least ideas behind developing oxytocin based therapies. And now we know that there's circuits and there's molecules that can achieve the same thing. And this opens up a whole swath of new targets for interventions for social deficits that manifest in a wide range of diseases.
Sam: So, although the animals could still pair bond without oxytocin signaling, which, don’t get me wrong, is still a huge deal, because it implicates a bunch of other molecules in pair bonding or, in our case, what we call “love,” Dev and his colleagues did see that milk production was somewhat impaired in the females.
And as they’ve continued on with this work, they’ve found other differences in the patterns of social behavior in prairie voles without oxytocin receptors, including that the initial pair bonding behaviors in both males and females are different and that they are social with animals of the opposite sex who they’re not bonded to, which is not at all the norm.
It is fascinating to see how we form these bonds. But to me, it’s also interesting to see how we maintain them.
Zoe Donaldson: So a lot of the work that's been done with prairie voles has really focused on: “how do you form a bond?” This is the fun part of bonding, this is the hedonic falling in love, staying awake too late part of things. And it's building this foundation where you start associating one particular person or, in the case of a vole, another vole, with this really pleasurable, intensely satisfying and hedonic experience.
So eventually our relationships give way … we're no longer staying up late thinking about our partner or staying on the phone, just kind of murmuring things all night long and things like that. So instead we start building lives together. We move in together, maybe we have kids and we start sort of divvying up the chores and our lives. And what happens is that partner becomes this really important source of reward, motivation, support.
They almost act as this sort of safe base from which we can explore the world, because we know we can always go back to them and they can make us feel better. And so there's almost these two phases where you fall in love, you form a bond, and then you maintain that bond over time.
Deboki: Zoe and her lab were interested in figuring out what the brain does to help us to maintain these bonds over time.
Zoe Donaldson: One of the studies that really intrigued me was a human fMRI imaging study. So in these kinds of studies, they look at where oxygen goes in the brain, and then this tells you a little bit about what brain regions are active. And so in this imaging study, they had people in a scanner and then they told those people that they were either holding hands with their partner or they were holding hands with somebody that they didn't know.
Deboki: They found that when people thought that they were holding hands with their partner, there was increased activity in the nucleus accumbens, a region of the brain central to reward and pleasure seeking behavior, where dopamine is released. Zoe was intrigued. So she and her lab set up a study in prairie voles, placing tiny fiber-optic sensors in their nucleus accumbens. If the sensor picked up a release of dopamine, it would light up.
In one scenario, a female vole had to press a lever to open a door to get into the room where her partner was. In another, she had to climb over a fence to get to him.
Zoe Donaldson: And what we found is if we asked them to work to gain access to their partner, there was more dopamine being released if they knew they were about to get access to their partner than if they knew they were about to get access to some vole that they didn't know. And the same was true when they actually reunited with their partner. When they reunited with their partner, it’s very adorable. They basically crawl all over each other and there's this nice big jump in dopamine. Whereas when they do the same thing with some animal that they don't know, there isn't that corresponding jump in dopamine levels.
Sam: That flood of dopamine seems to be what helps keep the deep bond between prairie voles alive after they bond, serving as a sort of chemical imprint. But what happens to that chemical imprint after loss?
Zoe Donaldson: We often form multiple relationships over our life course, and sometimes we even face the loss of a loved one — the death of a loved one or a partner — which is incredibly painful. And so another question that my laboratory is very interested in is what are the things that happen in your brain that help you to adapt to this loss? … And so we sort of stepped back and we said, okay, so what we know about prairie vole pair bonds is that they're very exclusive.
So if a prairie vole is bonded to another prairie vole, it can't form a bond with some other vole. So we did a study where we paired a whole bunch of voles and then we separated them for different amounts of time before giving them a new partner in order to ask, “how long do they have to be separated from their first partner before they can form another bond?”
Deboki: What they found was that after four weeks the intense flood of dopamine is gone and the vole can form a new bond with a new partner. Maybe four weeks doesn’t sound like a lot but for an animal with a life expectancy of around a year and a half, that’s quite long. On a human timescale, it’s around four years.
Zoe Donaldson: Whatever made that sort of chemical imprint on the brain had eroded over that time period, essentially erasing that specialness, if you will. And so we think that this is one of the ways that the brain naturally adapts to the loss of a partner. And in the case of a vole, this then leads to a state where they could potentially form another bond.
Sam with Zoe Donaldson: Which is very sad, but also happy in a way. If you were going to extrapolate that to people, what would you say?
Zoe Donaldson: So I tend to think of loss as a wound that you have to heal from. And I think the important implications for our work is really to those subset of individuals who have trouble with that wound healing. This is a new diagnosis in the psychiatric Diagnostic and Statistical Manual that's called prolonged grief disorder, and it refers to a subset of individuals that have a really hard time adapting to the loss of a loved one. And so we think of this as almost a stalling of the normal adaptive process that most people undergo for most losses. And so from my perspective, if we can better understand how the brain normally adapts to loss, maybe we can facilitate that for people who are having difficulty integrating the loss and reengaging with life.
Sam with Zoe Donaldson: It is one of these things where it's like, oh, it's sad to think that your brain is rewiring after loss because you care about the person that you lost, but at the same time, if it didn't, these are the implications.
Zoe Donaldson: Sometimes when I give talks, I say “unrequited love sounds romantic, but it's not something you actually want to experience for very long.”
Sam with Zoe Donaldson: Yeah, absolutely not. Sounds painful.
Zoe Donaldson: Exactly.
We have this framework for thinking about what happens in the brain after a vole loses their partner that eventually allows them to adapt that loss and move on. As the next step forward, how can we manipulate this process to either facilitate it or impair it, to give us one more layer of understanding and one step closer to developing therapeutics, whether it be pharmacological agents, so medicines that you take in a pill, or therapy, or some combination of the two?
Deboki: So you might be wondering how dopamine and oxytocin fit together in our understanding of pair bonding or love. There’s still a lot that’s unknown, but Zoe told us that research is pointing to oxytocin playing a key role in our initial drive to bond to a specific person or for a vole to bond with one very special vole, and then dopamine really helps reinforce the bond that is formed.
We could talk about the complexities of love all day, but we’re going to leave you with something that has nothing to do with love but does have to do with oxytocin.
Daniel Quintana: For a very long time, oxytocin has been seen as exclusively a social hormone. For a long time it was seen as a prosocial hormone that is just associated with positive things. More recent research suggests that that's not necessarily the case, that it is also associated with some non pro-social behaviors such as gloating or taking pleasure at the misfortune of other people. So there is what's been called the dark side of oxytocin.
Deboki: In addition, oxytocin has another side that is not social at all. There’s research focused on the importance of oxytocin in metabolism as well as in bone regeneration. And some of Daniel and his lab’s research on where in the brain oxytocin receptors are located has implicated oxytocin in behaviors like learning.
Daniel Quintana: Our work in generating new hypotheses is leading to some upcoming trials where we're actually looking at the role of oxytocin in non-social learning. So how we learn, how we make decisions, how we change our mind, those types of things. And we're also looking at the neural basis of how these things actually occur. And by doing that, we're looking at how oxytocin influences how our neurons communicate with each other and how oxytocin may strengthen or weaken the communication.
Sam: This is pretty cool stuff. I feel like every time we do an episode that focuses on the brain there’s a moment where we just kinda shrug and say “we don’t know anything about X.” But in working on this episode I loved how much I learned that we do know. Like oxytocin, dopamine, love, attachment … it’s all very complicated. But the strides researchers are making in understanding how they’re connected and how that could lead to advances in medicine is so important and really exciting to see happening.
Sam: Do you want to go, since yours is tiny, tiny, and then I'll go?
For my Tiny Show and Tell, I just have some news that I heard, I was really excited about it, and I'm hoping that it leads to good things. This is that the world's first malaria vaccine rollout has started, and it started in Cameroon. We're recording this on January 25th, and I believe it started this week, so by the time people are listening to this episode, it'll have been going for at least a few weeks. The vaccine itself is called RTSS, better known as MOSCORIX. I don't know how that's supposed to be pronounced. It's going to be given to children.
There have already been successful trials of the vaccine in Ghana, Kenya, and Malawi between 2019 and 2021, so it's been tested and now they're just trying out this rollout. Hopefully, it will go well because having a malaria vaccine would be really, really important, and in particular, many of the deaths from malaria happen in Africa, and they particularly happen to children under five. One of the things that the people behind the rollout are stressing is that this is actually just one measure among several, so the vaccine doesn't cut down on the need for other malaria prevention measures, like using an insecticide treated bed net while sleeping. It's not, on its own, necessarily going to get rid of malaria, but I'm just excited for any public health measure that can help reduce the effects of malaria overall.
Sam: That's really happy and exciting news. I actually, for my Tiny Show and Tell, I have additional exciting news for humanity.
Sam: We're both very uplifting today. It is an episode about love so, I'm like, maybe we're just in a mood?
Deboki: We're feeling it.
Sam: I want to talk about some very cool new findings related to delivering drugs in the brain. For many conditions, you just need to get drugs into your bloodstream, they go where they need to go. That's pretty easy. But if you want a drug to actually act in the brain, it needs to pass through this membrane called the blood-brain barrier, which separates our circulatory system, our blood, from our brain. It's super important for protecting our brain from dangerous pathogens, toxins, other unwanted stuff that might be circulating in our blood, but it makes it hard to deliver drugs, including this recent Alzheimer's drug called Aduhelm, I think is how you say it, that has been shown to be able to remove fibrous deposits called amyloids that will form the brain plaques in Alzheimer's disease. What these researchers found was a way to open up the blood-brain barrier for a really short period of time while delivering the drug.
They did this by using tiny gas bubbles to really help delicately open up the barrier while also using pulses of ultrasound, which uses sound waves traditionally to help researchers get an image of what's happening internally. Sometimes it's an ultrasound if someone is pregnant or ultrasounds to the brain, or really you can image a lot of things using ultrasound. When the barrier was open, 32% more plaque was dissolved in people, and then in animal studies where they could actually radioactively label the drug and then really quantify how much was getting in, they found that opening the barrier allowed five to eight times more antibody to enter the brain, which is incredible.
The other thing about this is that these are really pretty straightforward, simple techniques, they don't require new wildly expensive equipment, which means that they really have the highest chance of widespread success, actually making a difference for Alzheimer's patients and maybe other patients who need drugs to pass through the blood-brain barrier for whatever condition that they're dealing with. I love stuff like this where it's like this is actually technology that is available and accessible in a lot of places across the globe, and that means that there's just such a better chance that this will actually make an impact. You can come up with some wild technology that no one can afford and that isn't available anywhere, and it's like, "Good for you. Great. What are we going to do with that?" But this is pretty simple comparatively.
Sam: Good news today.
Deboki: Yeah, these are our Valentines from science, from the world of medicine.
Thanks for tuning in to this week’s episode of Tiny Matters, a prduction of the American Chemical Society. This week’s script was written by Sam, who is also our executive producer, and was edited by me and by Michael David. It was fact-checked by Michelle Boucher. The Tiny Matters theme and episode sound design are by Michael Simonelli and the Charts & Leisure team.
Sam: Thanks so much to Zoe Donaldson, Dev Manoli, and Daniel Quintana for joining us. Have ideas for episodes? Science-y things you just need to share? Email us: email@example.com. If you want another way to support the show, buy one of our coffee mugs! We’ve left a link in the episode description. You can find me on social at samjscience.
Deboki: And you can find me at okidokiboki. See you next time.