Prairie voles can find partners just fine without the ‘love hormone’ oxytocin

Prairie voles have long been heralded as models of monogamy. Now, a study suggests that the “love hormone” once thought essential for their bonding — oxytocin — might not be so necessary after all.

Interest in the romantic lives of prairie voles (Microtus ochrogaster) was first sparked more than 40 years ago, says Devanand Manoli, a biologist at the University of California, San Francisco. Biologists trying to capture voles to study would frequently catch two at a time, because “what they were finding were these male-female pairs,” he says. Unlike many other rodents with their myriad partners, prairie voles, it turned out, mate for life (SN: 10/5/15).

Pair-bonded prairie voles prefer each other’s company over a stranger’s and like to huddle together both in the wild and the lab. Because other vole species don’t have social behaviors as complex as prairie voles do, they have been a popular animal system for studying how social behavior evolves.

Research over the last few decades has implicated a few hormones in the brain as vital for proper vole manners, most notably oxytocin, which is also important for social behavior in humans and other animals.

Manoli and colleagues thought the oxytocin receptor, the protein that detects and reacts to oxytocin, would be the perfect test target for a new genetic engineering method based on CRISPR technology, which uses molecules from bacteria to selectively turn off genes. The researchers used the technique on vole embryos to create animals born without functioning oxytocin receptors. The team figured that the rodents wouldn’t be able to form pair-bonds — just like voles in past experiments whose oxytocin activity was blocked with drugs.

Instead, Manoli says, the researchers got “a big surprise.” The voles could form pair-bonds even without oxytocin, the team reports in the March 15 Neuron.

“I was very surprised by their results,” says Larry Young, a biologist at Emory University in Atlanta, who was not involved with the study but has studied oxytocin in prairie voles for decades.

A key difference between the new study and past studies that used drugs to block oxytocin is the timing of exactly when the hormone’s activity is turned off. With drugs, the voles are adults and have had exposure to oxytocin in their brains before the shutoff. With CRISPR, “these animals are born never experiencing oxytocin signaling in the brain,” says Young, whose research group has recently replicated Manoli’s experiment and found the same result.

It may be, Young says, that pair-bonding is controlled by a brain circuit that typically becomes dependent on oxytocin through exposure to it during development, like a symphony trained by a conductor. Suddenly remove that conductor and the symphony will sound discordant, whereas a jazz band that’s never practiced with a conductor fares just fine without one.

Manoli agrees that the technique’s timing matters. A secondary reason for the disparity, he says, could be that drugs often have off-target effects, such that the chemicals meant to block oxytocin could have been doing other things in the voles’ brains to affect pair-bonding. But Young disagrees. “I don’t believe that,” he says. “The [drug] that people use is very selective,” not even binding to the receptor of oxytocin’s closest molecular relative, vasopressin. 

Does this result mean that decades of past work on pair-bonding has been upended? Not quite.

“It shows us that this is a much more complicated question,” Manoli says. “The pharmacologic manipulations … suggested that [oxytocin] plays a critical role. The question is, what is that role?”

The new seemingly startling result makes sense if you look at the big picture, Manoli says. The ability for voles to pair-bond is “so critical for the survival of the species,” he says. “From a genetics perspective, it may make sense that there isn’t a single point of failure.”

The group now hopes to look at how other hormones, like vasopressin, influence pair-bonding using this relatively new genetic technique. They are also looking more closely at the voles’ behavior to be sure that the CRISPR gene editing didn’t alter it in a way they haven’t noticed yet.

In the game of vole “love,” it looks like we’re still trying to understand all the players.