The identity of an odor is deconstructed by the nose and represented by a unique, spatially invariant, combination of structures called glomeruli in the olfactory bulb, the first relay station for olfactory information in the brain. An olfactory map of activity is thus generated in the olfactory bulb. How does the brain reconstruct the identity of an odor from a pattern of active glomeruli in the bulb? Our approach to answer this question combines molecular biology and mouse genetics to map and characterize the neural circuits used by the brain for processing olfactory information.

Using our knowledge of the biochemistry of signal transduction pathways, we have designed a system for trans-synaptic labeling of neurons in the mouse. The core of the system is a synthetic signaling pathway that will be genetically introduced into all neurons in the animal. This signaling pathway translates the activation of an engineered receptor fusion protein into expression of a reporter gene that can be visualized. Specificity will be achieved by genetically modifying the olfactory sensory neurons that express a given odorant receptor to secrete the ligand for the engineered receptor into their synapses. Binding of the ligand to its receptors on the projection neurons that form synapses with the modified olfactory neurons will activate the signaling pathway, leading to expression of the reporter gene only in these cells. In this manner, only this subset of projection neurons will be visualized. Our experimental design is not limited to tracing experiments. Since the system is modular, it can be readily adapted for functional studies, in which we will genetically modify a given neural circuit and study the behavioral consequences. Ultimately, these studies may elucidate the mechanisms used by the brain to identify odors and to translate this information into behavioral outputs.