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Genes Switched, Antisocial Mouse Turns Warm And Fuzzy

For the first time, researchers have transformed an antisocial mouse into a more social animal by genetically manipulating the distribution of a specific receptor in the brain.

Neuroscientists at Emory University 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. The work is described in the August 19 issue of Nature.

In trying to uncover the neurochemical mechanisms behind bonding and attachment, Drs. Tom Insel and Larry Young have long studied vasopressin, a naturally-occurring peptide hormone produced in the brains of most mammals, including humans.

In voles, the scientists previously showed vasopressin to be important in male social and reproductive behaviors, determining the real influence to lie in the distribution of the hormone's receptors and not in 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," says Dr. 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 that was 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, pair bonding and paternal care, whereas in the closely related montane vole, which is polygamous, vasopressin fails to influence social behavior.

An explanation for these different vasopressin effects between prairie voles and montane voles was suggested several years ago when Insel's lab reported a different pattern of vasopressin receptors in the brains of these two species.

This 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 promoter region of the vasopressin receptor gene. This region of the gene is 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," says Dr. Insel, "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 socio-ecological conditions," says Dr. Insel.

Young and Insel have recently studied vasopressin receptors in non-human primates and now plan to focus on variation in the receptors in humans. The fact that virtually every form of human psychiatric disorder is characterized by abnormal social attachments makes this work important.

Yet remarkably 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, schizophrenia, Tourette's syndrome and Alzheimer's disease, all of which result in isolation and detachment.

The study was funded by grants from the National Institute of Mental Health.

[Contact: Kate Egan ]






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