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
]
18-Aug-1999