Molecular mechanisms of olfaction in mammals

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DESCRIPTION (provided by applicant): In mammals, volatile odorants are detected by olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) of the nose. In response to odorants, OSNs transmit signals to the olfactory bulb (OB) of the brain, which relays signals to the olfactory cortex (OC). The OC sends information to yet other brain areas involved in odor perception and the emotional and physiological effects of odors. Odorant detection in mice is mediated by ~1000 different odorant receptors (ORs), each expressed by a different subset of OSNs. ORs are used in a combinatorial manner to detect odorants, thereby allowing discrimination of a seemingly unlimited variety of odorants. However, we recently identified a second family of fourteen chemosensory receptors in the mouse OE. Genes encoding these receptors, called `trace amine-associated receptors' (TAARs) are present in mouse, human, and fish, and are found in both fish and mouse OE. Like ORs, individual mouse TAARs are expressed in unique subsets of OSNs that express only that receptor, and OSNs with the same TAAR are dispersed within certain OE domains. These findings indicate that there are multiple subsets of OSNs that use different TAARs rather than ORs to detect chemosensory stimuli. Screening of TAARs with diverse odorants revealed ligands for several TAARs, all of which are small volatile amines. Strikingly, at least three mouse TAARs recognize amines found in urine. One detects a compound linked to stress while the other two detect compounds enriched in male versus female urine, one reportedly a pheromone. The evolutionary conservation of the TAAR family suggests that this family may have a chemosensory function distinct from ORs. Ligands identified for TAARs thus far hint at a function associated with the detection of social cues. In the proposed studies, we will further investigate the roles played by TAARs in the mouse. To identify compounds recognized by TAARs with unknown ligands, we will screen a wide variety of amines for activation of individual TAARs. We will also use calcium imaging of TAARs expressed in a cell line to ask whether most or all TAARs detect compounds in mouse urine and, if so, whether those compounds are differentially represented in the urine of mice of different genders, ages, or genetic backgrounds. We will then examine how TAAR signals are represented in the OB. First, we will use TAAR gene probes to examine to number and positions of glomeruli that receive input from individual TAARs. Next, we will use mice coexpressing axonal reporters with selected TAARs to determine whether or not there are TAAR-specific glomeruli. Then, we will use c-Fos to examine the responses of individual TAAR glomeruli to identified TAAR ligands as well as to mouse urine from different sources. Finally, we will prepare mice that coexpress a transneuronal tracer with single TAAR genes to investigate how TAAR signals are organized in the OC.Project Narrative The mechanisms that the brain uses to perceive the world around us and to learn and remember are unknown. We will investigate the mechanisms that underlie the sense of smell to gain insight into these questions.