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Zoe Donaldson, Ph.D.
Department of Molecular, Cellular, and Developmental Biology & Department of Psychology and Neuroscience
University of Colorado Boulder
Dana Grantee: 2018-2021
Fascinated by the central role of love in art, literature, and everyday life, Zoe Donaldson decided to investigate the neuroscience of this powerful emotion. As a first step, she spent her graduate studies studying prairie voles, to understand the genetic elements that contribute to the evolution of monogamy. At that time, the field of social neuroscience was still small, so Donaldson decided to broaden her perspective during her postdoctoral research. Working with mice, she developed transgenic technologies to manipulate the expression of specific genes in brain regions during development.
Donaldson’s interest in the neuroscientific basis of love didn’t wane, and when she started her lab at the University of Colorado Boulder, in 2016, she realized that she was in the ideal position to take advantage of newly emerging optical techniques to investigate brain function, and started applying these methods to voles. In a study published in 2020, Donaldson and her group used these techniques to find out how reuniting with a partner plays out in their brain.
Why are voles a model system for studying love?
We humans are innately driven to fall in love, we don’t choose to fall in love. This innate ability to fall in love is biologically hardwired, but it appears in only a few species. So to study bonds, we use prairie voles, instead of mice or rats, because prairie voles are one of only about 8 percent of mammalian species that are capable of forming pair bonds. In my lab, we study two species of voles: prairie voles and meadow voles. Prairie voles are “monogamous,” while meadow voles are “promiscuous,” which gives us a great opportunity to look for what’s different between these two species. Prairie voles and meadow voles share overlapping home ranges and look identical, but have vastly different behaviors. So what in their brain guides this difference in behavior? Why do prairie voles form pair bonds, and why don’t meadow voles form pair bonds?
How is such a pair bond defined?
A pair bond is the scientific term for what we would describe in humans as “falling in love.” We use this term because we don’t want to anthropomorphize too much and we don’t have a way to ask a vole: did you fall in love? Still, we use behavioral proxies that are similar to human behavior when humans are in love. Proximity-seeking is the complex term we use to describe the voles’ behavior, and we humans exhibit this behavior with our partners all the time: we seek them out, we want to be near them, we want to cuddle. The voles huddle, we cuddle—it’s quite similar and strikingly cute to watch, I’ll be honest.
Is this pair bond specific to partners and different from family bonds?
Yes, we think of pair bonding as a mating-based bond. It is more similar to a spousal relationship in humans. I study pair bonds because they are an extreme version of bonds—the type of extremity described in the story of Romeo and Juliet, deciding to end their lives if they can’t be together. I want to study a powerful version of a behavior, something that is easy to study because it is so extreme. But a lot of the rules that we have learned from pair bonds apply to other types of relationships and other types of bonds.
Take, for example, oxytocin. Work with voles was central to identifying oxytocin as an important hormone for mediating pair bonds. It turns out that oxytocin is also important for parent-offspring relationships. Much of what we learn in prairie voles is informative for the broader spectrum of social relationships that we form. (see also the article “Oxytocin: the Molecule of Love, Trust, Morality, and Sociality?”
You are bringing new, imaging-based techniques to the study of pair bonds. Which approaches are you choosing?
We’ve implemented in vivo calcium imaging, and we essentially use tiny microscopes that fit onto the animal’s head. Peering through a lens into the brain, we can look at neurons that have been genetically modified so that they flash whenever they are active. This allows us to see, in real-time, what is happening inside the vole’s brain as it is running around.
How do you use this technique in your experiments?
In our most recent paper, we gave the vole a choice: do you want to spend time with your partner or would you rather hang out with an opposite-sex vole that you have never met before? We know that in bonded pairs, a vole spends more time with its partner than with an opposite-sex individual that it doesn’t know. Within vivo calcium imaging, we can now look at their brain as the voles are making this choice and ask: how is this being computed? What are the activity patterns that underlie this decision to be with a partner?
What activity pattern did you expect to observe in bonded pairs?
We hypothesized that we would observe more activity within a certain brain region, the nucleus accumbens, when pair-bonded voles are with their partner. This was driven by an observation in humans using fMRI, which looks at blood oxygenation levels as a proxy for how active a brain region is. In that study, people in an MRI scanner believed they were either holding hands with their partner or with a stranger. When they thought they were holding their partner’s hand, the researchers saw an increase in blood oxygenation levels within the nucleus accumbens, indicating that area was more active. We figured that this was analogous to prairie voles choosing to huddle with their partner. So going in, we hypothesized that we would see more activity in the voles’ nucleus accumbens.
No, it turns out that this is not the case. In the voles, we do not see more overall activity in the nucleus accumbens when they are with their partners. The reason is probably that blood oxygenation levels are an indirect metric of neural activity, whereas with the voles we were looking directly at individual cells within the brain region.
We then decided to take a more nuanced view. Since we can look at individual cells in voles, we wanted to ask: what is the neural code that encapsulates a vole’s decision to go towards its partner? So rather than looking at the brain when the vole is simply hanging out with its pair-bonded partner, we looked at the vole’s decision to go and join a partner versus going to join a stranger.
What neural code did you uncover?
We found that a subset of neurons in the nucleus accumbens is active when the animal decides to run towards its partner, and a different subset of neurons fires when the animal decides to approach a stranger. With time, this network gets bigger: After two voles have bonded, and as the bond matures, more neurons fire when the animal decides to run to its partner. Also, prairie voles, like humans, show differences in how strong their bonds are, and the strength of a bond correlates the size of this network.
This suggests that there is a change in how your brain is used after you form a bond. Neurons change their firing properties to encode the information that is relevant to approaching the partner; this information may be the desire to be with the partner
Do you know what this neuronal network does?
What we know at this point is that the network is active when voles run towards their partner, and that the network gets bigger after they form a bond, compared with the network’s size before they bonded. So, we still have a lot to figure out; for example, what information is the network exactly encoding? Is it encoding the desire to be with a partner, which grows over time? We want to tease out whether the brain grows fonder with time.
How are you interrogating voles’ desire to be with their partners?
Prairie voles have an incredible drive to be with their partner. So we are following up on our findings by doing operant training: We ask the animals how much they really want to be with their partner. The animal has to press a lever, a door opens, and it gets to huddle with its partner for 90 seconds. Then we can change the rules of the game—in the next round of the experiment, the animal has to press the lever two or three times. In this way, we can quantify how hard the animals are willing to work to get to their partners.
And the answer is: really, really hard. We found that it isn’t just a preference for who the vole wants to huddle with, it’s who the vole is willing to work for in order to spend time huddling. This behavior is a little bit like when we have long-distance relationships and are willing to go to ridiculous extremes to be with our partner. Pressing a lever is our proxy for measuring this willingness. If the network encodes the desire to be with a partner, which grows over time, we could be able to tease it out with this lever-pressing task. Are the same cells active when voles run towards their partner as are active when they press a lever to be with their partner? The concordance of activity across those tasks would suggest that these are important neurons for driving voles to seek out their partners—and presumably driving humans to find the people they love.
What’s the next step in your research?
We are trying to move towards causality. We are developing new techniques that would allow us to manipulate neurons and ask: How does the animal’s behavior change if we turn these neurons on or if we turn these neurons off? This is a difficult and challenging thing to do, but we want to bring together genetic technologies with imaging technology. Doing so would allow us to investigate, for example, what having no proper oxytocin signaling would mean for your brain as you are trying to develop relationships.
You liken a vole’s willingness to press a lever to our willingness to travel long distances, to join a partner. To what extent can insights from prairie voles be transferred to humans?
Insights have been transferred before, with the finding that oxytocin is involved in pair-bonding in voles. Because of this insight, oxytocin has started to be used as a potential therapeutic. Several clinical trials are probing the use of intranasal oxytocin application, for example during couples therapy. The idea is that oxytocin boosts social saliency, that it’s making you feel more empathy and trust towards your partner, and is so boosting the efficacy of these therapies. Oxytocin is an example of how this type of work in prairie voles has translated into a better understanding of human social behavior.
Are you interested in applying your findings on pair bonding to human behavior?
I would like to translate some of what we learn into the human context, specifically considering what happens when you have formed a bond, but the bond can’t be fulfilled anymore. This could be because of a breakup or the loss of a loved one. The motivation or desire to be with the individual doesn’t go away immediately, but now you can’t be with them. We want to get a sense of what this frustration looks like within the brain. We are starting a series of experiments, asking what happens when a vole presses a lever, expecting to join its partner, but the partner is not there. The results could shed light on the human context.
This is important because currently, people who experience severe forms of grief receive treatments that are used for treating depression or PTSD, but these treatments don’t work for them. We have no handle on how the brain might encode this pathological form of grief. Our experiments will, I hope, give us some insights into the processes that have to go right in order to adapt to the loss of a partner. In this way, we can get some insights into what might be going wrong in people that are having difficulties with it. But our work has even broader implications, I think, for many neurological and neuropsychiatric disorders, as many of these disorders are characterized by deficits in social behavior.
Can your insights from prairie voles also help us handle the seasons of social distancing we are experiencing at the moment?
It helps to know that loneliness is a real biological phenomenon. You have a need to be with the people you love, in the same way you have a need for water or for food. So what do you do in the middle of a pandemic? It’s one of those hard questions because there isn’t a fulfilling answer. There is no magic bullet. Try to take care of yourself in as many ways as possible and maintain those social ties. But what we are going through, the loneliness, is normal. Of course it is, but we don’t think about it like we think about our bodily needs of eating, drinking, breathing air—even though we are just as hardwired in our need for social interaction.
Jennifer L. Scribner, Eric A. Vance, David S. W. Protter, William M. Sheeran, Elliott Saslow, Ryan T. Cameron, Eric M. Klein, Jessica C. Jimenez, Mazen A. Kheirbek, Zoe R. Donaldson, A neuronal signature for monogamous reunion. Proceedings of the National Academy of Sciences May 2020, 117 (20) 11076-11084; DOI: 10.1073/pnas.1917287117