The perception of sensory information plays a critical role in social and sexual behavior. Olfactory stimuli have been shown to elicit important responses such as intermale aggression, sexual arousal, puberty acceleration, and estrus synchronization. In many mammals, including humans, these communication stimuli have been identified as small hydrophobic, volatile molecules. These communication chemicals are present at high concentrations in biological fluids and activate specific sensory neurons by binding to specialized receptors of nasal neuroepithelia. Although there have been considerable advances in elucidating the nature of these receptors and the transduction pathway that leads to the propagation to the brain, we know very little about the critical process for managing these hydrophobic molecules in the hydrophilic nasal mucus. A specific class of lipocalins, Major Urinary Proteins (MUPs) 4 and 5 (nasal MUPs), are present in the mucus and have been shown to selectively bind a number of small hydrophobic odorants and pheromones in vitro. However, the in vivo function of the nasal MUPs as well as the other nasal lipocalins, remains unresolved largely due to the absence of molecular genetic tools. Several hypotheses have been postulated regarding their potential function including: 1. MUPs function as ligand-specific transporters delivering odorant and/or pheromones to receptor sites, 2. MUPs function as scavengers removing odorants from the receptor after transduction, 3. MUPs act as buffers preventing saturation of the receptors, and 4. MUPs act as transducers that activate the receptor. The overall hypothesis of this proposal is that nasal MUPs serve to selectively bind biologically meaningful hydrophobic molecules and are critical for odorant detection and subsequent behavior. The primary goal of this proposal is to apply integrated genetic, physiological and behavioral methods to elucidate the physiological role for nasal MUPs in mammalian chemical communication and the mechanisms whereby these compounds influence biologically relevant social behaviors. This approach to studying perireceptor events may open new avenues of research in the chemical senses and expand our understanding of normal and abnormal sensory function beyond the olfactory neuron. ? ? ?
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