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The Skaggs Institute
for Chemical Biology


Scientific Report 2008




Molecular Biology of Olfaction

L. Stowers, P. Chamero, K. Flanagan, D. Logan, T. Martin, F. Papes, A. Kaur

Appropriate behavior 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.

Olfactory 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.

Publications

Logan, D.W., Marton, T.F., Stowers, L. Species specificity in major urinary proteins by parallel evolution. PLoS ONE 3:e3280, 2008.

 

Lisa T. Stowers, Ph.D.
Assistant Professor

Stowers Web Site