News and Publications

Molecular Biology of Olfaction

Every breath samples the environment for chemical information, determining the quality of food, warning of danger, and confirming safety. The sense of olfaction involves 2 types of neurons: those that mediate an evocative perception that varies with each individual's experience and those that regulate stereotyped innate social behaviors such as aggression and mating. Neurons that elicit perception of odorants reside in the olfactory epithelium and relay chemical information through activation of cAMP-responsive channels. Recently, we showed that behavior-generating neurons are located in the vomeronasal organ and respond to pheromones through a cascade that ultimately activates C-type transient-receptor-potential 2 (TRPC2) channels. We are using a molecular genetic approach to characterize the function of these pheromone-responsive neurons.

Through extracellular recordings, we showed that neurons from mutant mice that lack TRPC2 do not depolarize in response to natural sources of pheromones. Behavioral assays with these animals revealed that this pheromone response is necessary for both intramale aggression and sex identification. Additionally, we identified a subpopulation of the TRPC2 neurons that also expresses a family of class Ib MHC receptors. Biochemical experiments revealed that these receptors interact with pheromone receptors, and behavioral investigations with mutant animals indicated that these neurons are necessary for intramale aggression. We are currently identifying other unique molecular subpopulations of pheromone-responsive neurons, and through genetic ablation, biochemistry, and electrophysiology, we are assigning biological function to each neuron type.

A full characterization of the repertoire of chemosensory neurons will be essential in understanding the logic of olfactory information coding. To this end, we are investigating a third class of olfactory neurons that lack both the cAMP and the TRPC2 signaling components. Analysis of these neurons by transcriptional profiling, and then molecular genetics and biochemical studies, is being used to identify their role in olfactory function.

The response to pheromones is integrated in the amygdala, a highly conserved structure that is implicated in regulating social behavior in humans. The molecular mechanisms that generate behavioral responses have not been identified. In collaboration with the Genomics Institute of the Novartis Research Foundation, San Diego, California, we are using an unbiased approach of screening mice with random point mutations for behavioral defects in the pheromone-response pathway. In addition to identifying animals with defects in the sensory neurons, we expect to identify mutations in specific neurons in the amygdala, providing molecular tools to further understand general principles of neurons that govern complex social behavior.

Publications

Loconto, J., Papes, F., Chang, E., Stowers, L., Jones, E.P., Takada, T., Kumanovics, A., Fischer Lindahl, K., Dulac, C. Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class Ib molecules. Cell 112:607, 2003.

Stowers, L., Holy, T.E., Meister, M., Dulac, C., Koentges, G. Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science 295:1493, 2002.