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Identification of the pheromone ligands and sensory neurons that
mediate male-male aggression in the mouse.
Pablo Chamero
In mice, pheromones serve as signals between individuals to regulate their
social behavior. The identity of pheromones that are sufficient to regulate
individual behaviors are largely unknown. Isolation of these chemical ligands
and their target sensory neurons is essential to elucidate the logic of the
underlying neural circuit that generates behavior.
We have chosen to define the components that are sufficient to generate male-male
territorial aggression. Previous behavioral analysis has revealed that activating
pheromones are excreted in adult male urine. We have now shown by behavioral
analysis and direct activation of sensory neurons that at least two physically
distinct ligands are sufficient to regulate male-male aggression. We have purified
and analyzed one of these classes of ligands and found the activity dependant
on the presence of the major urinary protein (MUP) complex which is known to
be comprised of 18kD proteins that bind small molecule ligands. Previous studies
have shown that these ligands are sufficient to activate both VNO and MOE neurons
while the protein is thought to either stabilize the small molecule in the
environment or carry it into the nasal cavity. Using calcium imaging of primary
vomeronasal neurons we show that the protein is necessary for neuronal activation.
Furthermore, the MUP complex specifically activates the basal, Galpha0, vomeronasal
neurons in contrast to the small molecule ligand which, when dissociated from
the MUP protein, has been shown to activate the apical Galphai2 neurons. Finally,
we are unable to detect activation of MOE neurons by the MUP complex suggesting
that the aggressive behavior generated by detection of the MUP complex occurs
exclusively through VNO neuronal circuits. Our results have identified the
MUP protein complex as novel pheromone ligands that are sufficient to mediate
male-male aggression.
We expect that the identification of both the stimulating ligand and the responsive
sensory neurons will provide the tools to manipulate and therefore study the
molecular and neuronal pathway that regulates male-male aggressive behavior.
