High-Tech Tools Reveal Secrets of the Social Brain

Research tools are emerging that may open the way to a true neurobiology of complex social behavior, a new basic science for psychiatry, said Thomas R. Insel, M.D., director of the National Institute of Mental Health.

In a lecture at APA's 2004 annual meeting in New York City in May, Insel said that laboratory research with animals, as well as studies linking genetic, cellular, and systems-level functioning in normal and abnormal human behavior, is beginning to illuminate phenomena—maternal and paternal behavior, attachment, aggression, social interaction—long considered so complex as to be impervious to a truly neurobiological understanding.

“Over the last decade what we have begun to see is the emergence of a social neuroscience that now really has the power to provide important information that could be relevant to the major mental disorders and could be the basis for a translational research for psychiatry,” Insel said.

Social Memory Studied

Insel outlined several areas of scientific inquiry that illustrate the emerging social neuroscience. These include animal studies looking at the neurobiology of social memory and attachment and research involving humans with autism or other disorders that impact on social interaction. He concluded by describing how brain imaging may help in locating and mapping the“ social brain,” the specific areas of the brain critical to social interaction.

Both attachment and social memory— the processing of information necessary to recognize and remember social contacts— are distinctive social functions of the brain that rely on two critical neuropeptides: vasopressin and oxytocin.

Insel explained that these two peptides have a similar genomic structure, are found uniquely in mammals, and—as distinct from other neurotransmitters—appear to be slow-acting modulators essential to a range of complex social and sexual behaviors.

Oxytocin, already known to be integral to a range of maternal behaviors, appears to be especially critical in modulating social memory. The latter can be studied by comparing the amount of time a test mouse spends meeting and greeting a newcomer mouse under different test conditions.

Under normal conditions, for instance, mice spend two to three minutes in a ritual of investigation when a newcomer mouse is introduced; later, when the same mouse is reintroduced and recognized, the test mouse will spend less than half that amount of time investigating.

When a test mouse is genetically engineered to be missing the gene for oxytocin, however, its social memory is critically impaired, Insel explained. Thus, unable to recognize a mouse it has already met, it spends as much time investigating the newcomer at the second introduction as at the first.

Moreover, imaging of the mouse brain reveals that in situations of social interaction, one particular area of the brain rich in neuroreceptors for oxytocin, the medial amygdala, becomes especially active. The same area fails to become active in the “knockout” mice who have had the gene for oxytocin deleted; likewise, when oxytocin is injected directly into the medial amygdala of the knockout mice, their social memory is restored.

“This now gives us the ability to identify individual cells important to making a social memory,” Insel said. “From the brain's perspective, social memory is like no other form of memory. It has different genes and different cells, and it involves different circuits.”

Attachment Based on Chemistry

Oxytocin and vasopressin appear to be likewise critical in the formation of attachments, an hypothesis borne out by experimentation using two laboratory animals with distinct mating and social tendencies—the prairie vole and the montane vole.

The prairie vole is a highly social creature that lives in burrows with other voles, forms a partner preference, and mates for life. In contrast, the montane vole lives in solitary burrows and breeds promiscuously.

In the laboratory these tendencies are replicated: when placed together in cages, prairie voles form a partner preference and mate; later, given free run of the cage, the male spends more time with its tethered female mate than with a stranger vole. In contrast, the male montane vole, under the same test conditions, spends as much time with a stranger vole as with the vole with whom it has mated.

“The point about mating is an important hint,” Insel said.“ It tells us there is something going on in mating for prairie voles that is different for montane voles, something that is activating a system that [motivates them to form] lifelong pair bonds.”

To test the role of the oxytocin and vasopressin, which are both released powerfully during mating, researchers placed prairie voles together but prohibited them from mating. Then they posed the question: Given injections of oxytocin, vasopressin, or cerebrospinal fluid (CSF) as a control fluid, would the animals still form pair bonds?

For the males, neither oxytocin nor CSF worked. However, vasopressin had a powerful effect on the amount of time the male voles spent with a partner as opposed to a stranger, suggesting that the peptide is sufficient in the formation of attachment.

The inverse test was then performed to test whether vasopressin is essential: the prairie voles were placed together and allowed to mate, but they were given a vasopressin or oxytocin antagonist or CSF as a control.

Insel said the researchers found that whether given the CSF or an oxytocin antagonist, the prairie voles mated and formed a long-term pair bond. Yet when given the vasopressin antagonist, they mated normally but failed to form the long-term bond.

The conclusion? “Vasopressin appears to be both necessary and sufficient for longterm pair-bond formation,” Insel said.

Microvariation Occurs in Promoter Region

Contrary to expectations, however, when the promiscuous montane vole was injected with vasopressin, it still did not adopt the monogamous ways of the prairie voles. While the peptide caused the montane vole to adopt some anomalous behaviors, such as scratching and self-grooming, it failed to make it more social.

The explanation, Insel said, lies in a microvariation in a promoter region—the portion of a gene that determines whether a protein will be expressed in a given cell— of the gene that codes for vasopressin in montane voles. Because of that variation, the vasopressin receptors will be expressed in the promiscuous montane vole in the lateral septum of the brain; in the monogamous prairie vole, they are found in the ventral pallidum.

“What that tells you is that the same peptide will have completely different properties in these two species,” Insel. “These are parts of the brain that have completely different circuits with completely different outcomes. So it's not at all surprising that one species does a lot more scratching than the other species, which given the same peptide at the same dose falls in love.”

Eyeballs Reveal Clues

Complementing the animal research are human studies involving children and adults with autism, Asperger's syndrome, or Williams syndrome—conditions that variously affect social abilities and processing of social information.

He described innovative research at the Yale Child Study Center using infrared video oculography, a technology for tracking the movement of the eyeballs, showing how people with autism see, or don't see, social information. When viewing a movie laden with social interaction, most people naturally focus on eyes; people with autism, however, appear unable to focus on eyes and fix their gaze instead on mouths, thus missing much of the visual social information.

An illustrative contrast to the disorder is provided in Williams syndrome, a rare genetic disorder involving intellectual deficits and some physical abnormalities. In contrast to autism, people with Williams syndrome have an unusually keen social sense and are often remarkably empathic. And, curiously, very young children with Williams syndrome develop a “boring gaze,” an intense fascination with the eyes.

Insel also demonstrated for his audience an ingenious research tool for mapping how ambiguous information may be processed in the brain differently by people with Asperger's, a disorder marked by deficiencies in social communication and skills.

A short video clip depicted the movements of three ambiguously drawn figures, something like the movement of Xs and Os in the diagram of a football play. To most viewers, the “story” that emerges from the video is a familiar one of attraction and rejection: one figure seeks to partner with another, which rejects the suitor in favor of a third. To people with Asperger's, impervious to socially laden information, the movements of the figures are likely to be inscrutable.

Insel added that functional magnetic resonance imaging reveals how socially laden information activates particular areas of the brain—the left and right lateral fusiform, areas that are believed to respond to visual images of faces.

Together, he said, the animal and human research points the way toward a true map of the social brain, from genes to cells to brain systems to behavior.

“Putting all this together, you can actually begin to define something that looks like a brain network that is critical to processing social information and that is quite different from a brain network that you need for processing mechanical information,” Insel said.

“If you are interested in what is wrong in the brain of an autistic child who doesn't seem to see social events, this begins to define some of the likely characters in the same way that the comparative neurobiology provided oxytocin and vasopressin as reasonable candidates to look for in the neurochemistry of social motivation.” ▪