The Skaggs Institute
for Chemical Biology
Molecular Biology of Olfaction
L. Stowers, P. Chamero, K. Flanagan, D. Logan, T. Martin, F. Papes, A. Kaur
relative to the surroundings is necessary for survival; however, the neural mechanisms
that detect important cues in the environment, process the meaning of the cues,
and initiate the corresponding behavior are largely unknown. The neural code of
behavior is difficult to study because most future behavior is determined by
previous experience, which often differs subtly among individuals. These differences
in experience lead to variable perceptions and unpredictable behavior outcomes across
individuals placed in the same environment. The underlying neural circuits are therefore
correspondingly variable and dynamic. To ensure experimental clarity and reproducibility,
we study the neural circuits that underlie innate behavior.
stimuli are known to elicit innate behaviors in rodents. For example, when a male
encounters another individual in his environment, he detects and processes the emitted
chemical cues to determine the age and sex of the intruder. If the cues signal that
the intruder is a juvenile, the male will respond appropriately and not alter his
behavior. If the intruder is a female, he will court her, and if he detects a male,
he will respond with aggression. Innate behaviors are strong and universal, suggesting
they are driven by genetically programmed, invariant neural circuits.
We are investigating innate mouse behaviors
that are stereotyped and quantifiable. Just as a biochemical assay is used to map
and elucidate a metabolic pathway, we use innate behavior as a functional assay
to identify the corresponding ligand cues and mediating neurons. Although this approach
requires an unconventional research plan, it can be used to sort out and identify
the unique biological tools, ligands, and receptors essential for studies at the
cellular and molecular levels, the neural circuit that detects the environment and
generates appropriate behavior.
We have been isolating the chemical ligands,
pheromones, that specifically govern social behaviors such as aggression and mating.
These ligands are detected in rodents by neurons and mechanisms that are active
in all terrestrial vertebrates but are not functional in humans. To expand our investigation
of innate neural circuits, we are also elucidating the ligands and responsive sensory
mechanisms that promote maternal-infant behavior. This behavior is the defining
behavior of mammals, including humans. We expect that identification of the neuronal
code that generates this innate behavior in mice will enable us to directly investigate
mechanisms of innate behavior in humans.
We have isolated the source of pheromones
that promote maternal-infant behavior, a step allows us now to specifically activate,
and thereby identify, the population of sensory neurons dedicated to promoting this
behavior. Our findings suggest that this fundamental social behavior is governed
by a unique olfactory mechanism, unlike other pheromone-mediated behaviors, that
may have orthologous counterparts that are present and functional in humans. To
further investigate these mechanisms, we are manipulating activation of the
sensory circuit by activating and inactivating ligand receptors, signal transduction
elements, and ion channels to identify the neurons we find essential for behavior.
We are also fractionating the natural source of pheromones to purify the ligands.
Once purified, these molecules will allow us to investigate the kinetics of their
response and manipulate their properties to validate their role in promoting behavior.
We expect that our studies will provide the tools to expand our understanding of
the logic of neuronal coding of innate behaviors in mice and, additionally, investigate
the molecular mechanisms that underlie human social behavior.
Logan, D.W., Marton, T.F., Stowers, L. Species specificity in major urinary proteins by parallel evolution. PLoS ONE 3:e3280, 2008.