Monogamous Rodents Don’t Want “Love Molecule” To Pair Up

PRairie voles mate for life. Much like humans, once voles form a pair bond—typically with a member of the opposite sex—they live together, share parents, and even prefer each other’s company over that of other voles. Decades of research on the monogamous rodents led to the discovery of the so-called love molecule oxytocin, a hormone that studies have shown is crucial for forming social bonds in prairie voles, humans, and several other species.

But new research published today (January 27) in Neuron has turned 40 years of oxytocin research on its head by showing that voles lacking oxytocin receptors still form pair bonds. The finding may provide clues as to why researchers have had mixed success using oxytocin to treat conditions that disrupt social bonding, such as depression and autism, the authors say.

“I think it really needs to rethink and rethink what we think oxytocin actually does,” says Alexander Ophir, a neuroscientist at Cornell University who was not involved in the study.

See “Oxytocin for autism?”

Most of what neuroscientists know about social bonds between humans (as well as between other animals) has its roots in experiments with prairie voles (Microtus ochrogaster)—tiny, drab rodents native to central North America. The animals form pair bonds naturally and quickly, making them an ideal model species to study social bonds. And for decades, study after study has shown that oxytocin is critical to their pair bonding, since using drugs or siRNA (a technique that blocks gene expression) to disrupt oxytocin receptor function in adult voles always prevented bond formation. The literature was so fixed, says Zoe Donaldson, a neuroscientist at the University of Colorado Boulder who was not involved with the study but has worked with the researchers in the past, that she speculates that some people are questioning the necessity of the present would have asked.

See “Epigenetics plays cupid for prairie voles”

Devanand Manoli, co-author of the new study and a behavioral neuroscientist at the University of California, San Francisco, is not one of those people; He has been interested in studying the genetic basis of attachment in voles for the past 14 years. “Prairie voles are closely related to other promiscuous species, and yet they have these [unique] social behaviors, which supports this notion that these behaviors have a strong genetic component,” says Manoli. But until now, few research groups had performed genetic manipulations on prairie voles (although such manipulations are now ubiquitous in mice), due in part to the difficulty of such experiments. Tinkering with the genome of a new animal always requires “tailor-made” techniques, says Manoli.

After years of trying to create a transgenic vole, the introduction of CRISPR allowed Manoli to create voles that lacked the gene for oxytocin receptors, Oxtr, which then allowed him and his lab to study the receptor’s role in behavior . The researchers injected the CRISPR-Cas9 system into unicellular vole embryos, excised the oxytocin receptor gene and replaced it with a defective, mutated version. The resulting animals produced oxytocin but had no functional oxytocin receptors anywhere in their bodies. And yet the genetically modified voles displayed normal parenting and attachment behavior. They produced less milk than normal voles, meaning fewer of their offspring survived, and those that did tended to weigh less than normal vole pups, but the researchers found no other developmental or physiological differences.

“The era of ‘a gene affects a behavior’ is over,” says Ophir.

To examine potential behavioral abnormalities in the genetically engineered voles, the researchers performed a mate preference test. The voles were raised alongside their same-sex siblings. When they reached adulthood, the scientists mated them and put a female and a male in a cage for a week. Thereafter, the voles were moved to another three-compartment chamber. Researchers placed a vole, its pair-bonded partner, and an unidentified vole in three separate chambers. The vole’s mate and the unidentified vole were both tethered in place, while the original vole had access to all three chambers for a period of three hours, during which the researchers measured the time spent with its pair-bound mate compared to the unknown spent vole.

Kristen Berendzen, a postdoc in Manoli’s lab, recalls arriving at Manoli’s office with the news that the voles lacking oxytocin receptors spent as much time together as normal voles and therefore apparently formed normal pair bonds. “Something really cool is happening here,” she recalls Manoli’s words. “We were very much expecting to see at least some decline in bond formation,” says Berendzen. “The fact that we haven’t seen any effect [on bonding] was surprising.”

I think it really requires rethinking and rethinking what we think oxytocin actually does.

– Alexander Ophir, Cornell University

The researchers do not rule out oxytocin as important in forming social bonds and point out the key differences between their work and previous studies. In previous work, scientists disrupted oxytocin signaling in adulthood, while in the present study, the voles did not have the oxytocin receptor at all. While the authors say they don’t yet understand why voles can form pair bonds without the oxytocin receptor, they expect the voles to be able to compensate for the lack of oxytocin during development by activating other genetic circuits. “Perhaps not so surprisingly, the species has evolved multiple mechanisms to ensure that what is important for them to survive can actually take place,” says Manoli. They also speculate that the voles might exhibit some social deficits in a more complex or naturalistic environment.

Oxytocin is often used to treat social disorders but is not always effective; Ophir and Donaldson agree that the vole findings may offer a possible explanation as to why. The study’s authors speculate in the article that it’s possible that some social behavioral symptoms that humans experience stem from the as yet undiscovered alternative pathways formed by the voles, which lack oxytocin receptors, since oxytocin is essential for the formation of social Bindings not necessary is their attachments. And in such cases, the hormone may not have much of an impact on the symptoms simply because it is not the cause. Ophir and Donaldson also agree that the findings are particularly relevant in the context of development and the role of oxytocin may change based on early experiences.

Donaldson adds that the study’s finding that oxytocin is not required for attachment has translational potential, adding that it may be possible to “stimulate” social behaviors in individuals who do not enjoy social interactions , if researchers can understand and activate these compensatory mechanisms .

Manoli agrees, saying that in the future he wants to do similar studies in more natural settings and adopt some of the tools already established in mice to better understand how social memories are formed in the absence of oxytocin. Rather than dismissing the hormone’s therapeutic potential, he says the study “opens up opportunities to really make our interventions more targeted and specific” for conditions associated with social deficits.