Adam K. Dewan - US grants

DESCRIPTION (provided by applicant): Olfaction, the sense of smell, contributes significantly to quality of life and overall human health. Volatile chemicals in the environment are detected by a large family of odorant receptors, the largest repertoire of genes in the mammalian genome. The odorant receptor family comprises three phylogenetically distinct types of receptors: Class I and Class II receptors (comprising over 1000 genes), and a recently discovered family of Trace Amine-Associated Receptors or TAARs (14 genes). This small gene family is well-conserved in many mammalian species including humans, suggesting that TAARs have a unique and important role in odor perception. It has been speculated that the TAARs respond to volatile social cues. However, the functional properties of these receptors are poorly characterized. The goal of this proposal is to define the functional properties of TAARs in the intact mammalian olfactory system in order to test the hypothesis that these receptors respond specifically or preferentially to a subset of odorants (i.e. amines). I will generate several strains of gene-targeted mice in which the olfactory sensory neurons expressing defined TAAR genes and their associated glomeruli in the olfactory bulb are fluorescently labeled. I will then characterize the response profiles of the receptors by imaging odor-evoked activity from the genetically defined glomeruli. The proposed experiments will characterize for the first time the function of mammalian TAARs in vivo, and will serve as the first step in determining how these receptors contribute odor perception in mammals. PUBLIC HEALTH RELEVANCE: The sense of smell is critical for quality of life and overall human health. We are taking a novel approach to characterize how odorants are detected under normal conditions by a newly discovered class of olfactory receptors, the trace amine associated receptors. Our methods will allow us to characterize for the first time how molecular interactions at these receptors contribute to mammalian odor perception.

? DESCRIPTION (provided by applicant): Progress towards understanding mammalian olfactory coding has been hindered by: 1) our inability to identify receptors that make a measurable impact on odor perception and 2) the highly complex and distributed nature of higher order olfactory projections in the brain. Volatile odorants are detected by a large family o olfactory receptor genes in the mouse. This includes two families of canonical odorant receptors (ORs) containing over 1,000 members, and a small family of 14 Trace Amine-Associated Receptors (TAARs). We have shown that the TAARs play a critical role in the detection of amines-a class of compounds that elicits avoidance behavior in naïve (untrained) mice. Moreover, the TAARs are required for the aversive quality of the amines. Because a majority of TAARs project to a cluster of glomeruli in the dorsal olfactory bulb, the neural circuitry underlying amine aversion can be traced from a genetically identifiable starting point. Here I propose to identify projections from TAAR glomeruli to higher brain regions, and to define their functions in odor processing. Specific Aim 1 will map the projections of olfactory bulb output neurons that get input from the TAAR glomeruli. Specific Aim 2 will optogenetically silence TAAR specific input to individual olfactory regions in order to determine their role in amine detection and aversion. Achieving these aims will be a key first step in identifying higher order neural circuitry that contributes to odor valence and olfactory perception in mammals.