Pheromones Identified that Trigger Aggression
between Male Mice
A family of proteins commonly found in mouse urine is able to
trigger fighting between male mice, a study in the Dec. 6, 2007,
issue of Nature has found. The study, which is the first
to identify protein pheromones responsible for the aggression response
in mice, was funded in part by the National Institute on Deafness
and Other Communication Disorders (NIDCD), one of the National
Institutes of Health. Pheromones are chemical cues that are released
into the air, secreted from glands, or excreted in urine and picked
up by animals of the same species, initiating various social and
reproductive behaviors.
"Although the pheromones identified in this research are
not produced by humans, the regions of the brain that are tied
to behavior are the same for mice and people. Consequently, this
research may one day contribute to our understanding of the neural
pathways that play a role in human behavior," says James F.
Battey, Jr., M.D., Ph.D., director of the NIDCD. "Much is
known about how pheromones work in the insect world, but we know
very little about how these chemicals can influence behavior in
mammals and other vertebrates."
Researchers at Scripps Research Institute, La Jolla, Calif., and
Harvard University chose to study aggression for this study because
it is a strongly exhibited social behavior in male mice. Because
mouse urine had already been linked to aggressive behavior in males,
the team narrowed the field of pheromone candidates by separating
out progressively smaller compounds in the urine and studying their
effects on both mouse behavior and their ability to activate sensory
receptor neurons in the vomeronasal organ. The vomeronasal organ
is one of two locations in the mouse's nasal cavity that houses
sensory receptor cells that detect pheromones. The other location
is the main olfactory epithelium, the part of the nasal cavity
that also detects smells. Earlier research conducted by the group
had determined that receptor neurons from the vomeronasal organ
are required for the aggression response to occur.
To study behavior, the researchers swabbed the backs of neutered
male mice with the various pheromone candidates and placed them
in a cage with a normal male mouse. Neutered males are useful for
the study of aggression because they can neither emit nor detect
the aggression pheromones. Whereas normal males will begin fighting
as soon as they are placed together in a cage, neutered males remain
docile around normal males, and vice versa. If a neutered male
whose back has been swabbed with a pheromone candidate elicits
hostility in a normal male, the researchers know that the pheromone
candidate is responsible for the behavior.
Using a technique called calcium imaging, the team also studied
whether pheromone candidates were able to directly activate sensory
receptor neurons. Receptor neurons were removed from a mouse vomeronasal
organ, spread out on a Petri dish, and labeled with a substance
that changed color when the neuron was activated.
The researchers discovered that the protein family that comprises
the major urinary protein (MUP) complex in mouse urine is one of
two pheromones that can elicit the aggression response in male
mice. They also found that the MUP protein is recognized exclusively
in the vomeronasal organ, not in the main olfactory epithelium,
and activates a specific type of sensory receptor neuron. A second
pheromone was also found to elicit an aggression response in male
mice, however further study needs to be done regarding its make-up
and activity.
"There are about 20 members of the MUP family, and each mouse
expresses four to six of the members randomly," explains senior
investigator Lisa Stowers, Ph.D. "This creates a bar code
of individuality for each mouse. And we don't know whether the
proteins are actually coding for aggression per se, or whether
they're serving as a general cue of individuality for a male."
If the latter is the case, it could help explain why, unlike the
males, female mice don't show aggression when with a male. In addition
to investigating this question further, the team plans to explore
how receptor neurons sift through all of the cues in the environment
to detect the relevant cues to influence behavior and how those
sensory neurons are connected to the rest of the brain. They also
hope to learn more about the neural pathway itself — whether
one pathway in the brain is dedicated to one behavior, or whether
there are general pathways that can lead to a range of behaviors,
which may be modulated by a specific pheromone.
Other sponsors of this research include the Pew Charitable Trust,
Skaggs Institute, Helen Dorris Foundation, and the Basque Government
Post-Doctoral Research Fellowship.
The NIDCD supports and conducts research and research training
on the normal and disordered processes of hearing, balance, smell,
taste, voice, speech, and language and provides health information,
based upon scientific discovery, to the public. For more information
about NIDCD programs, see the Web site at www.nidcd.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
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