September 7 , 1999
Volume 52, No. 3
Insel, Young discover 'sociability gene' in prairie voles
For the first time, researchers have transformed an antisocial mouse into a more social animal by genetically manipulating a specific receptor in the brain.
Tom Insel, director of the Center for Behavioral Neuroscience, and Larry Young, assistant professor of psychiatry and behavioral science, created a "transgenic" mouse by inserting a gene from a prairie vole, a rodent species known for its fidelity and sociability. The new mouse showed the brain receptor distribution and even adopted the social behaviors of the gregarious prairie vole. Their work is described in the Aug. 19 issue of Nature.
Insel and Young have long studied vasopressin, a naturally occurring peptide hormone produced in the brains of most mammals, including humans, to try to uncover the neurochemical mechanisms behind bonding and attachment. In voles, the pair previously showed vasopressin to be important in male social and reproductive behaviors, determining the real influence to lay in the distribution of the hormone's receptors, not the amount of the hormone itself.
They found receptor distribution to vary greatly between species, with marked contrasts between monogamous and polygamous mammals. In the new research they inserted the vasopressin receptor gene from a monogamous vole into a less social, polygamous mouse. This is the first time that a single gene has proven sufficient to change complex social behaviors so dramatically.
"These transgenic mice really surprised us," said Young. "Not only did they show the prairie vole pattern of vasopressin receptors, but these mice responded to vasopressin just like prairie voles." While these transgenic mice were not monogamous, when given vasopressin they showed an increase in social contact with a female, a response not seen in normal mice.
Vasopressin has previously been shown to play a role in male social behaviors such as communication, aggression, sexual behavior and social memory. In monogamous species, such as the prairie vole, vasopressin facilitates affiliation, pairbonding and paternal care; in the closely related but polygamous montane vole, vasopressin fails to influence social behavior. Several years ago Insel's lab reported different patterns of vasopressin receptors in the brains of these two species, which might explain these different vasopressin effects.
The new research provides an intriguing explanation for the species difference in receptor distribution. The Emory team studied the molecular structure of the vasopressin receptor genes from several vole species and found a striking difference in the DNA sequence of monogamous and non-monogamous voles. In prairie and pine voles, which are monogamous and gregarious, the scientists discovered a long DNA sequence inserted in the vasopressin receptor gene's promoter region, thought to be important for determining when and where the gene is turned on. In this same region, the receptor gene was missing this insert in montane and meadow voles, which are promiscuous and frequently live in isolation.
To determine if this sequence difference was important for the distribution of vasopressin receptors in the brain, the Emory team incorporated the prairie vole vasopressin receptor gene with its long promoter sequence into the genome of mice, which are naturally much less social than prairie voles. In the resulting transgenic mice, the vasopressin receptor was expressed in a pattern that resembled what they had found in the prairie vole brain. Moreover, these transgenic mice when given vasopressin responded with increased social behavior, exactly as prairie voles but different from normal mice or montane voles.
"What is really intriguing about this," Insel said, "is that a change in the promoter sequence of a single gene can lead to a new pattern of receptor expression in the brain and then result in this profound difference in something as complex as social behavior."
Although a multitude of genes are likely to be involved in the evolution of monogamy, this work is an important step in beginning to identify the links between DNA sequences, brain chemistry and social behavior. "Perhaps it will turn out that mutations in this same gene have occurred many times in evolution, leading to alterations in patterns of social interaction and facilitating monogamy under special socioecological conditions," said Insel.
Young and Insel recently studied vasopressin receptors in nonhuman primates and now plan to focus on variation in the receptors in humans. Virtually every form of human psychiatric disorder is characterized by abnormal social attachments, yet very little is known about social bond formation-its anatomy, chemistry and physiology remain unmapped territories. Discovery of such information could be clinically relevant for treatment of autism and schizophrenia, which result in isolation and detachment.
The study was funded by grants from the National Institute of Mental Health.