�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,� says James F. Battey, Jr., director of the
National Institute on Deafness and Other Communication Disorders (NIDCD)
of the National Institutes of Health, which provided funding for the
study. �Consequently, this research may one day contribute to our
understanding of the neural pathways that play a role in human
behavior. 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.�
The Complex Puzzle of Brain Function
Identifying the chemical pathway of signals that make their way
through the neurological system is not easy. One of the challenges for
scientists studying brain circuits is that the brain is constantly
changing. How a brain detects and then responds to the scent of a
particular food, for instance, evolves as the animal learns about that
food.
But certain behaviors such as aggression responses between male mice
tend to be the same each time they are triggered, suggesting a steady
pathway through neurological circuits. So, the Stowers group has
focused a research program on understanding the aggression pathway as
a general model for brain response.
As a first step in the current study, the group sought to identify
specific chemical triggers for aggression in mice, which other
researchers had shown involved urine. The Stowers group separated out
several classes of chemicals within the urine, then individually
swabbed each class onto the backs of castrated mice to determine which
could spark an aggressive response by another male. Castrated males
lose the ability to elicit aggression on their own, so any such
response could be attributed to the added chemicals.
Using this experimental setup, the researchers were able to show
specific compounds triggered aggression. Upon examination, the
scientists found that these compounds fell into two distinct chemical
groups-low molecular weight and high molecular weight proteins.
Particularly intriguing were the high molecular weight compounds, as
few high molecular weight compounds exist in urine and none had ever
before been shown to act as pheromones. The Stowers group focused on
these for the remainder of the study.
Tracing Phermones� Path
Next, the Stowers lab sought to discover the effect of these high
molecular weight compounds on two neurological organs that could
potentially convey the pheromone signals to the brain. The first,
called the vomeronasal organ (VNO), is located above the roof of the
mouth in the nasal cavity. The second is the main olfactory epithelium
(MOE), found under the eyeball at the top back portion of the nasal
cavity.
Which of these two organs is the main starting point for the
aggression pathway is somewhat controversial. Stowers' group had shown
in past work that mice genetically altered to lack the VNO did not
have aggression responses, suggesting this organ plays a key role, but
other researchers had made similar findings with knockout mice lacking
the MOE.
To further explore this aspect of signal processing, the Stowers team
used an assay of their own design that allows the isolation of
individual VNO neurons and MOE neurons and measurement of their firing
in response to a given chemical cue. The researchers found that, when
exposed to high molecular weight compounds, VNO neurons fired
indicating that these are the sensory neurons that mediate aggressive
behavior. Moreover, the group was able to provide details about both
specific neurons and compounds, and further, identify the subset of
VNO neurons that fired in response to four specific high molecular
weight proteins acting together.
Stowers adds that while the work elucidates the VNO vs. MOE debate,
the current study does not settle it, because the yet-to-be-tested low
molecular weight compound class could function via the MOE instead of
the VNO. This could make sense because the smaller compounds are more
easily volatilized, making it easier for them to reach the MOE, which
resides much farther back in the nasal cavity than the VNO.
Interestingly, the four high molecular weight pheromone compounds
isolated are from a much larger class of proteins, but an individual
mouse only produces four, and the combinations produced differs among
individuals. In the past, this four-protein signature was thought to
be random, but Stowers says it is possible that different combinations
of the proteins could code for different responses.
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