Why do Voles Fall in Love?

Yerkes director and Emory neuroscientist Thomas R. Insel unravels the mystery of monogamy in the brain of a tiny rodent

"Might as well face it, you’re addicted to love."

—Robert Palmer

AT AGE EIGHTEEN, Thomas R. Insel had graduated from Boston University College of Liberal Arts and was headed into medical school. Distracted by the turbulent world of the late 1960s and feeling unready for more years of intense study, however, he took a year off and married his sweetheart, and the pair embarked on a trip to Asia.

"We left in 1969 and came back in ’70," recalls Insel, now director of the Yerkes Regional Primate Research Center and a neuroscientist who studies social attachment. "The Vietnam War was raging. We started in Hong Kong and worked in a TB clinic for the boat people for about six weeks, then we went very quickly through Southeast Asia, stopped in Cambodia for a while, Thailand for a while. Then we worked in a Mennonite mission hospital in India for a couple of months."

The unorthodox honeymoon sealed a lasting bond between Tom and Debbie Insel. Almost thirty years later, they have raised two children, and, they say, are still in love—a phenomenon that remains a mystery to them.

"I think there’s something about that shared experience, especially at a young age," Insel says. "People say you build bonds through adversity, and we certainly had our share of that. But I’m not sure if it was a biochemical event."

That mystery of undying love has, in part, driven Insel’s scientific inquiries for more than fifteen years. A psychiatrist turned neuroscientist, he and a team of researchers are tracing the pathways of the brain to find clues to social attachment that could one day solve the puzzles of autism and similar disorders. Their research subject is a palm-sized, fuzzy, brown rodent called the vole.

Insel and his colleagues primarily study male and female pair bonding in two species, the prairie vole and the montane vole. The two are 99 percent genetically alike, but that 1 percent divergence accounts for some dramatic differences.

Indigenous to the Midwest, prairie voles, Insel jokes, "represent in some ways the very best in Midwestern values." They mate for life, and the monogamous pairs nest together, often snuggling side by side. The male aggressively guards the female, and both are affectionate, attentive parents.

In contrast, the montane vole, a native of the Rocky Mountains, is a loner. The male and female do not share a nest and come together only briefly to mate. The male has no investment in the offspring. "They are what we consider the prototype of a promiscuous animal," Insel says.

"For us as neuroscientists interested in how the brain is organized, the question becomes, ‘Can we use these animals to understand the neural basis of monogamous behavior, particularly pair bonding, and how animals develop long-term social relationships?’ "

The prairie vole appealed to Insel as a subject because of how the creature begins to mate. The female remains sexually suppressed until at some point in her life—it could be at any moment—she is exposed to a particular pheromone in the urine of an unrelated virgin male. Suddenly, everything changes, and biology takes over. In twenty-four hours, the female’s uterus doubles in size, and her ovaries begin producing eggs. Both the male and female go from having no interest in sex to, as Insel says, "probably not thinking of anything other than sex."

The pair commences a twenty-four-hour period of mating. By the end of the day, both animals have undergone profound behavioral changes. Both show a preference to each other, eschewing the company of other potential mates. Ultimately, they both become intensely nurturing parents. The male, once gregarious and friendly, also becomes an aggressive guard of his mate.

"These changes never go away," says Insel. "It’s kind of like falling in love and never falling out. And all that is dependent on mating."

Insel and his colleagues wanted to know what it is about sex that prompts these changes. They theorized that two hormones released during mating might play a role in bonding. Oxytocin, a hormone found in all mammals, is associated with lactation, the contraction of the uterus during birth, and maternal behavior. Similarly, the hormone vasopressin engenders aggressive mate-guarding and paternal behavior in male mammals.

To find out whether these hormones, released during mating, are necessary for prairie voles to bond, the scientists blocked the release of oxytocin in a female and vasopressin in a male. In fact, the pair did mate, but they formed no lasting attachment.

Then the team conducted the converse experiment. They did not allow the animals to mate, but gave the female a dose of oxytocin and the male a dose of vasopressin. With the hormones but without sex, the prairie voles fell in love anyway.

"These hormones have the extraordinary ability to turn on or off the development of a pair bond," Insel explains.

Having concluded that the two hormones are somehow key to lasting, monogamous love, Insel and his colleagues turned to the montane vole, the promiscuous loner. They gave the female montane oxytocin and the male montane vasopressin to see if they would exhibit behavior similar to prairie voles.

"But all they did was scratch," says Insel. "They remained as uninterested in social interaction or bonding as ever. So the question had to be asked, ‘What is different about the brains of these two species that leads to such different responses to these hormones?’"

By comparing the brains of the prairie vole and the montane vole, the scientists learned that montane voles do already possess these hormones. The difference is that the receptors for the hormones are located in completely different areas of the brain.

"What makes it really intriguing," says Insel,"is that in the prairie vole, the receptors are found in circuits that are important for reward and reinforcement. Our theory is that when the monogamous animals mate and release these hormones, they get addicted to whomever they’re mating with—the odor, the sight, the experience. They want to go back again and again to the same mate."

It’s still just a theory, but the scientists have good reason to believe it will hold up to scrutiny. Recently, one of Insel’s postdoctoral fellows, Larry Young, created a transgenic animal by taking the gene for the receptor from the prairie vole and inserting it into a mouse brain.

"We’ve ended up with a kind of . . . experiment—a mouse that has a prairie vole vasopressin receptor in its brain," Insel says.

The animal did not become monogamous, but it did grow noticeably more social than a normal mouse.

"That really kind of blew us away," Insel says.

"In some way, this single gene could change the whole behavioral response to this neural peptide hormone. I find that sort of incredible, but we’ve done it with lots of [mice], and it looks real."

 

 

These kinds of breakthroughs are not new for Insel, who has made a career by being what he calls a scientific "misfit," pursuing inquiries no one else had thought to consider. After graduating from Boston University’s medical school in 1974, he completed four years of postgraduate training in psychiatry at the University of California in San Francisco and joined the intramural program of the National Institute of Mental Health (NIMH) in 1979. The program had been almost exclusively dedicated to the study of depression, but Insel "couldn’t imagine doing what everybody else was doing," he says.

So he turned to a study of obsessive-compulsive disorder, which had been classified as a neurosis, limiting treatment options to psychoanalysis. "No one in the American psychiatric establishment had any interest in it," says Insel, who became the first U.S. investigator to demonstrate the success of the drug serotonin as a treatment for the disorder. For this work, which established anti-obsessional drugs as a new research area for neuropharmacology, he received the A. E. Bennett Award from the Society for Biological Psychiatry in 1986.

As that field began to be crowded with new researchers, Insel took another unusual turn—this time toward neuroscience. Following a sabbatical with leading researcher Michael Kuhar, now chief of the neuroscience division at Yerkes, Insel used his newly learned techniques to shift from the clinic to the laboratory and take over the Section of Comparative Studies of Brain and Behavior within the Laboratory of Clinical Science of the NIMH. He and his colleagues began to explore the neurobiology of fear and anxiety, which led to their study of attachment behaviors.

"I became interested in learning how the brain mediates complex social behaviors that have mostly been the province of the humanities—the consequences of falling in love," Insel says. "It was moving from the whole human to looking at animals at the cellular and the molecular level. That sounds depressingly reductionistic, but it actually gets more bizarre and interesting as you get into the details."

Insel’s findings on oxytocin and vasopressin pathways in the rodent brain and his demonstration of their importance in social attachment won him the Curt Richter Prize from the International Society for Psychoneuro-endocrinology in 1991. In 1994, he was named director of Yerkes, professor of psychiatry in the School of Medicine, and adjunct professor of psychology in Emory College. His lab is now housed in the Woodruff Memorial Building of the medical school, where his attachment-behavior research continues.

The team of scientists is gradually moving toward applying its findings to primate brains, eventually including the human brain. They hope to gain new understanding of some of the most devastating human diseases—those that carry with them a particular aversion to human bonding.

"We’d like to find out whether oxytocin and vasopressin receptors are altered in cases of autism, Tourette’s syndrome, Alzheimer’s disease, and even schizophrenia—forms of psychopathology that are marked by the absence of attachment behavior," Insel says. "Since the core feature of autism is the inability to form those attachments, finding out the basis of social attachment in healthy animals and humans may be a place to begin."

While gene therapy for these disorders may be on the distant horizon, there is no simple analogy between the vole brain and the human brain. Humans are not dramatically transformed by mating in the way the vole is. People "fall in love" with cars, with food, with ideas and causes.

"We have this two-pound computer that sits on top of our hypothalamus, and that’s where it gets so much more complicated," Insel says. "It doesn’t mean that these hormones aren’t relevant; it just means that they’re not dictating our behavior as much as they would in the vole.

"But these are beautiful mechanisms for guiding and maintaining the path of evolution. We are now at the point of identifying specific genes that seem to direct certain species to monogamous behavior, and we hope we can move those genes around and change social behavior."

 

The mystery of undying love has driven neuroscientist Thomas R. Insel’s scientific inquiries for more than fifteen years. Does the pair-bonding of these voles hold the key?

 

I became interested in learning how the brain mediates complex social behaviors that have mostly been the province of the humanities—the consequences of falling in love.—Thomas R. Insel