What Can Rodents Tell Us About Why Humans Love?
A relative of the mouse may hold the key to understanding why human beings are one of the few mammals that seek lifelong mates
The pile of cotton and hamster bedding rises and falls steadily, as though the two prairie voles snuggled beneath are breathing in unison. In the wild, these “potato chips of the prairie” would be lucky to enjoy a few months of a partner’s company: Their snackable size makes them popular with weasels, hawks and snakes. But here in the breeding cages at Atlanta’s Yerkes National Primate Research Center, the voles can expect two or three years of blissful cohabitation, cranking out litters at the rate of one a month.
“Life is good,” says Larry Young, a Yerkes researcher who has been studying voles for nearly two decades. “They’ve got a mate. Nesting materials. No parasites. All the rabbit food they could want.”
Voles may look like animated pompoms with shining, watchful eyes to you and me, but Young and his colleagues see them as the key to understanding some of humankind’s most tender and mysterious impulses: why we care for our partners, coddle our children, even mourn our dead. The word “vole” is, after all, an anagram for “love.”
“My work is all centered around this central question: Why do we interact with others the way we do?” says Young. The answer, in his opinion, almost always comes down to neurochemistry, but it’s not an easy subject to study. Scientists can’t tamper much with the brains of humans or other living primates, and dead ones aren’t much use. Many molecular investigations of the mind have, for better or for worse, focused on the white laboratory mouse, but Young dismisses this animal model as “a bag of mutations.” After a century of inbreeding for medical research, it’s far too removed from nature.
The vole, closely related to lemmings and resembling hamsters, is a much newer experimental subject: The first prairie voles engineered to possess genes from another species came on the scene only in 2009. (They glowed green because they were tagged with a fluorescent jellyfish protein meant to signal visually that the DNA transfer had worked.) In 2012, scientists first read out the DNA in the voles’ genetic instruction book, or genome. And although in some ways the rodent is a bucktoothed burrower like any other, sometimes considered a pest by gardeners, it displays social traits that we think of as deeply human.
Most notable, voles—unlike 97 percent of mammals—are monogamous, forming bonds that last long after mating (often for life, albeit a short one). “Male and female come together, male courts the female so that she goes into estrus, and they mate,” Young explains. “And then something happens in the time when they mate, and in the hours after that, so that those two animals have bonded and they want to stay together always.” Rather than abandoning subsequent babies to fate, the males stick around to raise them. The female clearly expects this follow-through, yanking her guy by the scruff of his neck if he’s not doing his part. And when a partner dies, voles experience something akin to grief.
Perhaps most exciting of all, from a scientific perspective, prairie voles have near-identical cousins called meadow voles that share none of their social proclivities. By comparing the faithful rodents with their promiscuous doppelgängers, Young and his colleagues hope to reveal the neural circuits behind the prairie vole’s monogamous tendencies. “The prairie voles crave social contact, and the meadow voles don’t,” Young says.
An “extraordinary gift to science,” is how Thomas Insel, head of the National Institute of Mental Health and a pioneer in vole studies, describes the critters. “The experiment has already been done by nature,” he says. “What are the results? What was modified genetically in the brain to get this difference in behavior?”
To find out, Young uses a staggeringly sophisticated set of biomolecular tools, from genetic sequencing to transcriptomics.
But could an animal as humble as the prairie vole, only lately recruited from America’s plains, really have secrets to share about human conundrums such as infidelity, and perhaps even social disorders like autism? Absolutely, says Young, who himself began life as a provincial creature, born “a mile down a dirt road” in the sand and pine country of Sylvester, Georgia. (He still keeps a cabin there, where he hazes citified graduate students via goat skinning and other practices.) He had never even heard of DNA until after high school. Part of his interest in vole behavior and brain structure seems to stem from curiosity about his own life path: marriage, divorce, remarriage, five children and an ongoing love affair with neuroscience that’s taken him far from his rural roots.
The prairie vole first caught science’s eye in the 1970s, when the mammalogist Lowell Getz launched a routine population study in the alfalfa fields and bluegrass pastures close to the University of Illinois at Urbana-Champaign, where he taught at the time. To take the edge off the subzero temperatures at night, he and other researchers sometimes kept Jack Daniel’s in the study shed along with the data sheets and other materials. The alcohol was for the researchers’ own consumption; taste tests since have shown that prairie voles like liquor, and diluted whiskey may in fact have been good vole bait.
Cracked corn worked well enough in the traps, but the scientists did notice something unusual. Prairie voles frequently showed up in pairs, often a male and a female. Sometimes, the scientists would snare the same duo again months afterward. These couples made up some 12 percent of adult prairie vole catches, compared with just 2 percent among other trapped voles. To find out what was up, Getz outfitted a dozen prairie vole pairs with miniature radio collars powered by hearing aid batteries. Tracking their movements through the dense grass, he discovered that 11 of the 12 “couples” cohabited more or less permanently in subterranean dens, a behavior almost unheard of among rodents. Both members of the 12th couple had other partners in separate love nests. Getz had apparently captured the two mid-tryst.
Astonished, he took his findings to Sue Carter, a colleague at the University of Illinois who was working on hamster endocrinology. Female hamsters routinely slaughter and eat their sexual partners. “That’s what I thought was normal,” Carter recalls. She was unprepared for the voles’ attachment to their partners, or what turned out to be long-lasting and passionate mating sessions (“We had to put them on time-lapse video. No one could sit there for 40 hours!”).
But what makes the attachment so strong? How exactly does a pair forge its bond? Carter and others eventually homed in on the chemical messenger oxytocin—also a hormone associated with the perception of social cues, childbirth and maternal bonding. When a female prairie vole received an oxytocin injection in her brain, she huddled with her partner more and formed stronger bonds. Another hormone, vasopressin, related to territoriality, has been found to promote pair-bonding in males.
Perhaps, researchers proposed, evolution had piggybacked on well-established neural circuitry. If the hormones responsible for maternal behavior in females and territoriality in males were released during sex, they could foster this novel male-female bond. Prairie vole sex, for instance, involves an unusual amount of vaginal-cervical stimulation—probably an adapted behavior that triggers the oxytocin release normally associated with childbirth. Instead of bonding with a baby, the female bonds with her partner.
Subsequent studies showed that unlike the bond-eschewing meadow voles, prairie voles have oxytocin and vasopressin receptors in areas of the brain associated with reward and addiction. The voles’ brains are rigged to associate the reward of sex with the presence of a particular partner, just like “an addict learns an association with drug paraphernalia when getting high, so even his crack pipe becomes pleasurable,” Young says. He thinks that humans’ oddball face-to-face mating style, which highlights a partner’s unique physical features at the moment of reward, probably also serves to cement a pleasurable connection with a single individual.
The vole-bonding studies of the early 1990s intrigued Young, who had discovered molecular biology in college. After graduating, he did research in a Texas lab studying gender-bending whiptail lizards, whose fluctuating hormones allow them to shift between male and female behavior. He found he could change their behavior dramatically by injecting them with one hormone or another. When he went to Yerkes, at Emory University, he took along various techniques that could also decipher gene activity. In the first experiment of its kind in these critters, Young’s team put a prairie vole gene that codes for a vasopressin receptor into a virus, and then injected the virus into the reward centers of the meadow vole brain. The point? To see whether the alien DNA would alter the meadow vole’s behavior. It did: As the animals grew up, they began exhibiting pair-bonding behaviors. “We transformed a meadow vole into a prairie vole, behaviorally,” he says.
Long before he began his vole work, Young understood the power of the pair-bond: He married his high-school sweetheart on his 18th birthday. Now Young understands that any pair-bond depends on a suite of genes and brain chemicals, probably working alongside oxytocin and vasopressin. His most recent foray is into transcriptomics, a field focused on messenger RNA, the genetic material responsible for shuttling information from a cell’s DNA to its protein-making machinery. While the DNA of every cell in the body stays the same, the level of proteins produced by the translation of that DNA changes from one minute to the next. Young’s lab is attempting to watch how messenger RNA fluctuates as the mysterious prairie vole pair-bond is forged. Researchers “sacrifice” the animals at various stages in the bonding process, then extract the mRNA. If the mRNA signal indicates that genes are active during mating in prairie voles but not meadow voles, those genes become candidates for study. “We can design experiments to manipulate those genes,” Young says, “and determine if they are involved.”
Likewise, he’s eager to look at his newly sequenced prairie vole genome alongside the meadow vole’s genome, to find differences worthy of further investigation. The challenge comes in getting computers to compare and contrast such a vast amount of genetic information.
“There’s 50 years of work ahead of us, and a whole lot that we don’t know,” he says.
Here’s a dirty little secret: Prairie voles are socially, but not sexually, monogamous. As with human romances, pair-bonding doesn’t preclude what researchers call opportunistic infidelity, as evidenced by Getz’s two-timing 12th couple. This infidelity means that many males sire young outside the nest—and can accidentally end up raising someone else’s babies. (About 10 percent of young are from a father that is not their mother’s main suitor.) And just like in the human dating pool, some males don’t pair-bond at all. These footloose individuals are known as “wanderers.”
One of Young’s claims to fame is pinpointing a genetic difference between the career bachelors and the devoted partners. It’s found in a portion of a vasopressin receptor gene called a microsatellite, repetitive genetic material that for a long time was called “junk DNA.” Males with a long version of the microsatellite are superior pair-bonders, because they have more receptors in certain brain areas, while males with a short version might remain unattached.
Similar variation may matter among people, too. Swedish researchers genotyped nearly 2,000 adults and asked them about relationships. Men with two copies of a specific version of a vasopressin receptor gene were twice as likely to report a crisis in their marriage in the last year as men with one or zero copies. Their partners also expressed less satisfaction. Young hasn’t had his own gene analyzed: “I don’t want to know,” he says.
What he does want to know is more about what makes prairie voles different from one another. Can early life experiences make a difference? And could that difference shed light on human behavior and social disorders?
Katie Barrett, a graduate student in Young’s lab, pulls on multiple pairs of gloves as she leads me into a room full of adult voles. “They’re biters,” she says, by way of an explanation. The male voles in the room, each roaming in chambered arenas instead of ordinary cages, are in the middle of a partner preference test, the foundation of much of vole research. Along with the male, females collared with plastic zip ties are tethered at opposite ends of each arena. One female is the male’s mate, and another is a complete stranger. Though he may mate with both, a well-bonded male should spend much more time huddling with his partner. A computer program analyzes the movements of his pudgy little body, adding up the minutes.
Barrett has found that baby voles isolated from the licking and grooming of parents, an interaction known to stimulate oxytocin production, have trouble bonding with future mates—but only if the isolated voles also have a relatively low density of oxytocin receptors in reward areas of the brain. She is conducting tests to find out whether an oxytocin-boosting drug can protect the neglected animals’ social futures. “Can you intervene early in life and protect against this outcome?” Barrett asks.
Previous work had shown that the effects of oxytocin were stronger in females than in males, but in today’s test, males treated as pups are bonding quite well. “I wasn’t expecting that,” Barrett says. Early-life oxytocin release appears to build a stronger social brain in both sexes.
Voles, and by extension oxytocin, have begun to capture imaginations more widely, though the outcome is sometimes silly. There’s the self-help book Make Love Like a Prairie Vole: Six Steps to Passionate, Plentiful and Monogamous Sex, as well as a fragrance called “Liquid Trust,” a synthetic oxytocin spray marketed to “singles” and “salespeople” alike. Of course, Young points out, even if the spray works (and he is not saying it does), the wearer would inhale much more of the hormone than any potential target: “Who’s going to end up trusting who?” he laughs.
But some human uses are quite serious. One of Young’s primary interests is autism therapies. “Autism is a disorder where social cues are not as salient, kids are not motivated to interact with others and have difficulty reading emotions,” he points out. “All of these social things, oxytocin seems to stimulate.” Already synthetic oxytocin, administered through the nose, is being used in experimental treatments related to autism.
There’s good reason to be cautious about the curative powers of oxytocin, though. “In my own opinion, there hasn’t been enough preliminary data from animals,” says Karen Bales, who studies social bonding at the University of California, Davis, and worries about the consequences of exposing developing brains to the molecule. Bales and her colleagues have found that oxytocin exposure may inhibit later-life pair-bonding, particularly in male voles. And though some work, including in human beings, shows that the molecule may help sociality, others find that the effect depends on the individual and the situation.
“You have to beware of premature extrapolation,” says Insel, of the National Institute of Mental Health. “You want to be very careful and not assume that we are very, very large prairie voles.”
Less controversial, for the moment, is Young’s work in grief therapy. He and a German colleague recently studied what happens when voles and their life partners become separated. In rigorous stress tests, including ones that dropped rodents in a beaker of water, those that had just lost a partner struggled far less than the others. Instead, they passively floated, not seeming to care if they lived or died. In some ways, their symptoms resembled depression. “When animals form this pair-bond they become addicted to that partner, and when they lose the partner it is almost like withdrawal from a drug,” Young explains. “It’s a maladaptive consequence of an evolutionarily helpful thing. It’s love sickness.”
When researchers dissected the bereaved animals’ brains, they found elevated levels of a chemical called corticotropin-releasing factor, or CRF. If the bereaved animals’ chemical receptors were blocked, the voles behaved normally, struggling fiercely for life. “It helps us understand the neurocircuitry that may be involved in depression in general,” Young says.
He knows firsthand the pain of separation. About a decade ago, his first wife, his partner since high school, left him, taking their three children with her. For months he floated in a metaphorical beaker. “I lived in a house with no furniture,” he says. “I slept on a little kid’s mattress. I realized the consequences that happen when you lose someone you love, because I went through it. In the moment, when you’re going through it, you don’t think about experiments and things—these urges and drives are just happening.”
Young has since recovered his momentum. He recently founded the Center for Translational Social Neuroscience at Emory, which focuses on how basic animal research can inform new treatments for human social disorders, and convened an international meeting for vole researchers. A world map on the wall of his office highlights just how far he has traveled from his Sylvester “dirt road.” On one madcap journey to Madagascar, he and other researchers collected brain samples of two closely related species of plover, another animal with “love” in its name. One species is monogamous and the other isn’t. Young hopes to compare their neural wiring with that of the voles.
Perhaps most significantly, he also pair-bonded again, this time with another neuroscientist. Over dinner he and his partner discuss the finer points of his hormone work and how it relates to the human condition. Genetics and brain chemistry may shape every relationship, but they don’t make magic last on their own. “I still gotta remember the anniversary,” he says. “I still gotta buy the flowers.”