Is 'love Hormone,' Oxytocin, Also 'friendship Hormone'?

A new UC Berkeley study shows that the so-called love hormone, oxytocin, is also critical for the formation of friendships.

Oxytocin is released in the brain during sex, childbirth, breastfeeding and social interactions and contributes to feelings of attachment, closeness and trust. Never mind that it's also associated with aggression; the hormone is commonly referred to as the "cuddle" or "happy" hormone, and people are encouraged to boost their oxytocin levels for better well-being by touching friends and loved ones, listening to music and exercising.

But recent studies involving the prairie vole have called this love association into question. They've shown that oxytocin, which in the brain acts as a neuromodulator, is not essential for long-term mate bonding, or "social monogamy," or for parenting behavior, though without it, voles take longer to form such bonds.

Scientists focus on prairie voles because, like humans, they form stable and selective relationships. While most studies focus on mate bonds, the Beery lab at UC Berkeley is particularly interested in selective peer relationships, analogous to human friendships. Such studies could shed light on human psychiatric conditions, such as autism and schizophrenia, that interfere with a person's ability to form or maintain social bonds.

"Prairie voles are special because they allow us to get at the neurobiology of friendship and how it's similar to and different from other types of relationships," said Annaliese Beery, a UC Berkeley associate professor of integrative biology and neuroscience and senior author of the study.

Beery and integrative biology graduate student Alexis Black, one of two first authors of the study, found that prairie voles that lack oxytocin receptors take longer than normal voles to form peer relationships. Prairie voles that are close friends typically huddle side by side, groom and even sit on one another.

"Oxytocin seems to be particularly important in the early formation phase of relationships and especially in the selectivity of those relationships: 'I prefer you to this stranger,' for example," Beery said. "The animals that didn't have intact oxytocin signaling took longer to form relationships. And then when we challenged those relationships by making new groups, they lost track of their original partners right away."

The voles, genetically modified in the UC San Francisco laboratory of collaborator and co-author Dr. Devanand Manoli, also lacked the social rewards that normally come from selective attachments - they didn't work very hard to snuggle up with their friends and were less avoidant of and less aggressive towards strangers.

"In other words, oxytocin is playing a crucial role not so much in how social they are, but more in who they are social with, their selectivity," she said.

Lacking oxytocin receptors also changed the regulation of oxytocin availability and release in the brain, which the group documented using a novel oxytocin nanosensor in collaboration with postdoctoral fellow Natsumi Komatsu and Markita Landry, a UC Berkeley professor of chemical and biomolecular engineering.

"That helped us understand the feedback consequences of lacking this receptor, and how oxytocin signaling was altered in the brain," said Beery.

The study was published Aug. 8 in the journal Current Biology.

What social voles tell us about social humans

Beery has long been interested in social relationships in rodents, focusing primarily on the animals' seldom-studied peer or friendship relationships. While voles are her main focus, she believes studying similar behaviors across multiple species is key to determining what's species-specific versus generalizable across species.

To complement her laboratory research, she has conducted field studies comparing social behavior and oxytocin receptor distribution in the brain within and across species in a group of South American rodents and North American Belding's ground squirrels, which vary in whether or not they live in groups. She also recently began field tests of multiple vole species - there are about 50 worldwide - to compare their social behavior.

She suspects that in rodents such as voles, and perhaps in other mammals, the formation of peer relationships may have preceded the evolution of monogamous mating relationships.

"While most rodents prefer to interact with unfamiliar individuals, it turns out that the majority of vole species we've tested in our early trials form peer-partner preferences, which is what we call these selective friendships. So there seems to be this widespread tendency to bond," Beery said. "But only a couple of those species are also monogamous. Someday, I hope to be able to tell you, 'Do selective peer relationships precede the development of monogamy? Is that why monogamy has evolved so many times in this genus?' I think this familiarity preference is deeply rooted."

Beery was a co-author of a 2023 study led by Manoli that threw into question the association of oxytocin with sex and parenting. That study showed that prairie voles unable to respond to oxytocin exhibit the same monogamous mating, attachment and parenting behaviors as regular voles. Those voles had been genetically engineered to have no cellular receptors for oxytocin, and were the same voles used in the current study.

But while oxytocin isn't essential for eventual bond formation, additional studies by the same group published in 2024 showed that these receptor-deficient (or "null mutant") prairie voles took about twice as long as normal voles to establish a relationship with a potential mate.

Interested in how the lack of an oxytocin receptor affects voles' friendship bonds, as opposed to mating bonds, Beery and Black conducted three sets of experiments. In one, they tested how long it took for voles to establish a preference for a partner. Whereas normal voles take about 24 hours of close proximity to form a relationship that makes them choose that partner over a stranger, oxytocin receptor-deficient voles showed no preference in that amount of time, and took up to a week to establish a peer preference.

"Wild-type animals form this incredibly robust preference within one day of co-housing, but the null mutants have no sign of a relationship after 24 hours. After a week, they mostly get there, and the lifetime partners look no different from each other," Beery said. "Our conclusion from that experiment is that oxytocin isn't required to have a relationship, but it's really important in those early phases of a relationship to facilitate it happening quickly and efficiently."

They then put long-term pair-bonded voles in a party-like, mixed-group situation: an enclosure with other voles and many rooms connected by tubes. In such a situation, normal voles would hang out with known friends until they eventually started to socialize with strangers.

"They can all separate, they can all come together, or they can hang out in any combinations that they want," she said. "The wild-type animals keep track of who they know. It's like if I went to a party with a friend, I would stand near that friend for the first part of the party and then I might start to mingle. The voles that lack oxytocin receptors just mixed. It was as if they didn't even have a partner in there with them."

In the third experiment, they tested the strength of both peer and mate bonding by having the voles press levers to get access to either a friend/mate or a stranger.

"Female wild-type voles typically press more to get their partner than to get a stranger, in both peer and mate relationships. The oxytocin receptor deficient mutants also press more to get to their mating partner, but not for peer relationships," Beery said. "That makes sense at some level because we think mate relationships are more rewarding than peer relationships, or at least they depend more on reward-signaling pathways."

Lack of oxytocin signaling thus not only delays the formation of relationships, but also creates deficits in long-term peer relationships.

On the flip side, voles lacking oxytocin receptors were also less aggressive toward strangers and less avoidant of them.

"You can see contributions of oxytocin signaling to both sides of selectivity," Beery said. "On the prosocial side, it's involved in wanting to be with a known friend or peer, while on the antisocial side, it's aiding in rejecting an unfamiliar animal. We've seen effects of oxytocin on both affiliation and aggression in our other studies in prairie voles, and it parallels human findings on a role of oxytocin in in-group/out-group dynamics."

Oxytocin nanosensors

The researchers used a new oxytocin sensor developed in Landry's UC Berkeley lab to determine whether lack of an oxytocin receptor caused increases or decreases in oxytocin release. If oxytocin release increased in these voles, it could potentially interact with a receptor for a similar neuropeptide that is also involved in formation of social relationships, compensating for the absence of oxytocin receptors.

Landry, an associate professor in the departments of chemical and biomolecular engineering, neuroscience, and molecular and cell biology and a co-corresponding author of the paper, created these sensors from carbon nanotubes joined with specific single-stranded DNA sequences selected because they latch onto the oxytocin molecule and fluoresce. Komatsu and Landry found no excess of oxytocin in the voles' brains. In fact, oxytocin was being released in lower amounts from fewer sites in the nucleus accumbens, a key brain region for social reward across species.

Co-authors with Black, Komatsu, Beery, Landry and Manoli are Jiaxuan Zhao, Scarlet Taskey and Nicole Serrano of UC Berkeley, and Ruchira Sharma of UCSF. Beery's work was supported by the National Science Foundation (CAREER award 2239635) and the National Institutes of Health (R01MH132908). Komatsu is now an assistant professor at the University of Illinois.