'Love hormone'? Not so fast, new study suggests
A new study has raised questions about the role played by the so-called 'love horomone' oxytocin in mating behavior
The research found that voles bred to lack functioning receptors for oxytocin were still able to form strong pairs, produce young and nurse -- all behaviours previously believed to depend on the hormone.
Prairie voles are one of the few mammals that mate for life, and are often used to study social behaviours like pair-forming in animals.
In past studies, voles given drugs that stopped oxytocin being processed no longer formed pairs, and mothers failed to produce milk for their young.
Psychiatrist Devanand Manoli and neurobiologist Nirao Shah produced genetically altered prairie voles without working oxytocin receptors, and then observed how the mutant male and female voles behaved.
To their shock, the mutant voles appeared to have no difficulty pairing up with non-genetically altered partners, and mutant females could still deliver and nurse young, unlike those in the drug-driven studies.
"We were certainly surprised," said Manoli, an assistant professor at the University of California, San Francisco.
The results suggest that oxytocin is not the main, or only, driver of activities like partnering or nursing, he said.
"What the genetics reveals is that there isn't a 'single point of failure' for behaviours that are so critical to the survival of the species," he told AFP.
'Very complex behaviours'
That didn't mean there were no differences, however.
Some male mutant voles that paired with ordinary female partners didn't show the aggression towards interloping females that would normally be expected.
And while mutant females produced and nursed litters, some had fewer pups per litter than their counterparts, and fewer of their offspring survived to weaning, the paper published Friday in the journal Neuron explains.
Pups born to mutant mothers also tended to weigh less, suggesting that they were not able to nurse as effectively.
The study only involved pairing of mutant voles with "wild-type" partners, and the researchers said pairings with two mutant partners could produce different results.
Still, as a whole, the findings suggest a different picture of oxytocin's role in several important behaviours.
That could be because animals bred without the receptors developed "other compensatory pathways" that helped them pair up and nurse, said Shah, a professor at Stanford University.
But the researchers suggest it likely means oxytocin is only part of a set of genetic factors that control social behaviour.
"What I think our studies reveal is that there are multiple pathways that regulate these very complex behaviours," said Manoli.
Oxytocin has sometimes been suggested as a way to treat attachment disorders and other neuropsychiatric issues, but there is little settled science on how effective it is.
Now the researchers hope to investigate what other hormones and receptors may be involved in behaviours like pairing and nursing.
"These other pathways might serve as new therapeutic targets," Manoli said.
Fresh questions about oxytocin as the
Removing the Oxytocin Receptor Does Not Interfere with Monogamy or Giving Birth
Turning a decades-old dogma on its head, new research from scientists at UC San Francisco and Stanford Medicine shows that the receptor for oxytocin, a hormone considered essential to forming social bonds, may not play the critical role that scientists have assigned to it for the past 30 years.
In the study, appearing Jan. 27, 2023 in Neuron, the team found that prairie voles bred without receptors for oxytocin and showed the same monogamous mating, attachment, and parenting behaviors as regular voles. In addition, females without oxytocin receptors gave birth and produced milk, though in smaller quantities, than ordinary female voles.
The results indicate that the biology underlying pair bonding and parenting isn't purely dictated by the receptors for oxytocin, sometimes referred to as the “love hormone.”
“While oxytocin has been considered ‘Love Potion #9,’ it seems that potions 1 through 8 might be sufficient,” said psychiatrist Devanand Manoli, MD, PhD, a senior author of the paper and member of the UCSF Weill Institute for Neurosciences. “This study tells us that oxytocin is likely just one part of a much more complex genetic program.”
CRISPR Voles Pack a Surprise
Because prairie voles are one of the few mammalian species known to form lifelong monogamous relationships, researchers study them to better understand the biology of social bonding.
Studies in the 1990s using drugs that prevent oxytocin from binding to its receptor found that voles were unable to pair bond, giving rise to the idea that the hormone is essential to forming such attachments.
The current project emerged from shared interests between Manoli and co-senior author and neurobiologist Nirao Shah, MD, PhD, then at UCSF and now at Stanford Medicine. Shah had been interested in the biology of oxytocin and social attachment in prairie voles since teaching about the oxytocin studies decades earlier. Manoli, who wanted to investigate the neurobiology of social bonding, joined Shah’s lab in 2007 as a postdoctoral scholar.
For this study, 15 years in the making, the two applied new genetic technologies to confirm if oxytocin binding to its receptor was indeed the factor behind pair bonding. They used CRISPR to generate prairie voles that lack functional oxytocin receptors. Then, they tested the mutant voles to see whether they could form enduring partnerships with other voles.
To the researchers’ surprise, the mutant voles formed pair bonds just as readily as normal voles.
“The patterns were indistinguishable,” said Manoli. “The major behavioral traits that were thought to be dependent on oxytocin – sexual partners huddling together and rejecting other potential partners as well as parenting by mothers and fathers – appear to be completely intact in the absence of its receptor.”
Labor and Lactation
Even more surprising for Manoli and Shah than the pair bonding was the fact that a significant percentage of the female voles were able to give birth and provide milk for their pups.
Oxytocin is likely to have a role in both birth and lactation, but one that is more nuanced than previously thought, Manoli said. Female voles without receptors proved perfectly capable of giving birth, on the same timeframe and in the same way as the regular animals, even though labor has been thought to rely on oxytocin.
The results help to clear up some of the mystery surrounding the hormone’s role in childbirth: Oxytocin is commonly used to induce labor but blocking its activity in mothers who experience premature labor isn’t better than other approaches for halting contractions.
When it came to producing milk and feeding pups, however, the researchers were taken aback. Oxytocin binding to its receptor has been considered essential for milk ejection and parental care for many decades, but half of the mutant females were able to nurse and wean their pups successfully, indicating that oxytocin signaling plays a role, but it is less vital than previously thought.
“This overturns conventional wisdom about lactation and oxytocin that’s existed for a much longer time than the pair bonding association,” said Shah. “It’s a standard in medical textbooks that the milk letdown reflex is mediated by the hormone, and here we are saying, ‘Wait a second, there’s more to it than that.’”
Hope for Social Connection
Manoli and Shah focused on understanding the neurobiology and molecular mechanisms of pair bonding because it is thought to hold the key to unlocking better treatments for psychiatric conditions, such as autism and schizophrenia, that interfere with a person’s ability to form or maintain social bonds.
Over the past decade, much hope was pinned on clinical trials using oxytocin to address those conditions. But those results were mixed, and none has illuminated a clear path to improvement.
The researchers said their study strongly suggests that the current model – a single pathway or molecule being responsible for social attachment –is oversimplified. This conclusion makes sense from an evolutionary perspective, they said, given the importance of attachment to the perpetuation of many social species.
“These behaviors are too important to survival to hinge on this single point of potential failure,” said Manoli. “There are likely other pathways or other genetic wiring to allow for that behavior. Oxytocin receptor signaling could be one part of that program, but it’s not the be-all end-all.”
The discovery points the researchers down new paths to improving the lives of people struggling to find social connection.
“If we can find the key pathway that mediates attachment and bonding behavior,” Shah said, “We’ll have an eminently druggable target for alleviating symptoms in autism, schizophrenia, many other psychiatric disorders.”
Authors: Additional authors include: Ruchira Sharma, Rose Larios, Nastacia Goodwin, Michael Sherman and Isidero Espineda of UCSF, Maricruz Alvarado Mandujano, YiChao Wei, Srinivas Parthasarthy and Joseph Knoedler of Stanford, and Forrest Rogers, Trenton Simmons, Adele Seelke, Jessica Bond, and Karen Bales of UC Davis, and Annaliese Beery of UC Berkeley.
Funding: This work was supported by NIH grants R01MH123513, R01MH108319, DP1MH099900 and R25MH060482, NSF grant, 1556974, and philanthropy. For details, see the study.
About UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF's primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. UCSF School of Medicine also has a regional campus in Fresno. Learn more at https://ucsf.edu, or see our Fact Sheet.
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JOURNAL
Neuron
Prairie voles without oxytocin receptors can bond with mates and young
IMAGE: THIS IS A PHOTOGRAPH OF TWO PRAIRIE VOLES. view more
CREDIT: NASTACIA GOODWIN
The vital role of oxytocin—the “love hormone”—for social attachments is being called into question. More than forty years of pharmacological and behavioral research has pointed to oxytocin receptor signaling as an essential pathway for the development of social behaviors in prairie voles, humans, and other species, but a genetic study publishing in the journal Neuron on January 27 shows that voles can form enduring attachments with mates and provide parental care without oxytocin receptor signaling.
Prairie voles are one of only a few monogamous mammalian species. After mating, they form lifelong partnerships known as “pair-bonds.” Pair-bonded voles share parental responsibilities, prefer the company of their partner over unknown members of the opposite sex, and actively reject potential new partners. Previous studies that used drugs to block oxytocin from binding to its receptor found that voles were unable to pair-bond when oxytocin signaling was blocked.
Neuroscientists Devanand Manoli (@LabManoli) of UCSF and Nirao Shah (@Shah_Laboratory) of Stanford University wanted to know whether pair-bonding was really controlled by oxytocin receptor signaling. To test this, they used CRISPR to generate prairie voles that lack functional oxytocin receptors. Then, they tested these mutant oxytocin-receptor-less voles to see whether they could form enduring partnerships with other voles. To their surprise, the mutant voles formed pair-bonds just as readily as normal voles.
“We were all shocked that no matter how many different ways we tried to test this, the voles demonstrated a very robust social attachment with their sexual partner, as strong as their normal counterparts,” says Manoli.
Next, the researchers wondered whether oxytocin receptor signaling is similarly dispensable for its other functions—parturition, parenting (which, in prairie voles, is a shared responsibility between the two parents), and milk release during lactation.
“We found that mutant voles are not only able to give birth, but actually nurse,” says Shah. Both male and female mutants engaged in the usual parental behaviors of huddling, licking, and grooming, and were able to rear pups to weaning age.
However, the mutant prairie voles did have limited milk release compared to normal voles. As a result, fewer of their pups survived to weaning age, and those that did survive were smaller compared to the pups of normal prairie voles. The fact that the voles could nurse at all is in contrast to equivalent studies in oxytocin receptor-deficient mice, who completely failed to lactate or nurse, and whose pups consequently died within a day or so of being born. The authors hypothesize that this species difference could be due to the inbred nature of laboratory mouse strains in contrast to the genetically heterogenous voles. “It could be that inbreeding in mice has selected for a large dependence on oxytocin signaling, or this may represent a species-specific role of oxytocin receptor signaling,” says Shah.
When asked why their results differ from previously published studies that used drugs to block oxytocin receptor signaling, the authors point to the key difference between genetic and pharmacological studies: precision. “Drugs can be dirty,” says Manoli, “in the sense that they can bind to multiple receptors, and you don’t know which binding action is causing the effect. From a genetics perspective, we now know that the precision of deleting this one receptor, and subsequently eliminating its signaling pathways, does not interfere with these behaviors.”
“For at least the last ten years people have been hoping for the possibility of oxytocin as a powerful therapeutic for helping people with social cognitive impairments due to conditions ranging from autism to schizophrenia,” Manoli says. “This research shows that there likely isn't a magic bullet for something as complex and nuanced as social behavior.”
Another key difference is that, whereas most pharmacological studies suppress oxytocin receptor signaling in adult animals, this study switched it off when the voles were embryos. “We've made a mutation that starts from before birth,” says Shah. “It could be that there are compensatory or redundant pathways that kick-in in these mutant animals and mask the deficits in attachment, parental behaviors, and milk let-down.”
Working with prairie voles presented an obstacle, but one worth overcoming. Because prairie voles are not commonly used in genetic studies like laboratory mice, the team needed to develop all of their molecular tools and protocols from scratch. Now that they have these vole-specific pipelines and tools, the authors are excited about the doorways this opens, both for them and for other researchers.
“We're very happy to be part of a community and to have this technology that we can share,” says Manoli. “Now we have this trove that we can start to mine. There are so many other questions that prairie voles could be interesting and useful for answering, both in terms of potential clinical implications for models of anxiety or attachment and also for basic comparative biology.”
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This work was supported by the National Institutes of Health, National Science Foundation, Burroughs Wellcome Fund, Whitehall Foundation, AP Giannini Foundation Fellowship, Larry L. Hillblom Foundation Fellowship, and the Human Frontiers Science Program
Neuron, Berendzen, Sharma, Mandujano, and Wei et al. “Oxytocin receptor is not required for social attachment in prairie voles,” https://www.cell.com/neuron/fulltext/S0896-6273(22)01084-4
Neuron (@NeuroCellPress), published by Cell Press, is a bimonthly journal that has established itself as one of the most influential and relied upon journals in the field of neuroscience and one of the premier intellectual forums of the neuroscience community. It publishes interdisciplinary articles that integrate biophysical, cellular, developmental, and molecular approaches with a systems approach to sensory, motor, and higher-order cognitive functions. Visit: http://www.cell.com/neuron. To receive Cell Press media alerts, contact press@cell.com.
JOURNAL
Neuron
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Animals
ARTICLE TITLE
Oxytocin receptor is not required for social attachment in prairie voles
ARTICLE PUBLICATION DATE
27-Jan-2023
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