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,"
Devanand Manoli, UCSF
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."
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.
Berendzen, K.M., et al. (2023) Oxytocin receptor is not required for social attachment in prairie voles. Neuron. doi.org/10.1016/j.neuron.2022.12.011.