ADAPTIVE MORPHOLOGICAL AND FUNCTIONAL PLASTICITY IN THE MOUSE MAIN OLFACTORY EPITHELIUM AND BULB DURING CHEMICAL EXPOSURE: THE ROLE OF TRPM5-EXPRESSING MICROVILLOUS CELLS

Abstract

Sensory systems enable animals to monitor environmental changes and generate adaptive behaviors. Proper structural and functional maintenance of these systems is essential for survival. The olfactory system detects thousands of airborne odor chemicals and plays an important role in finding food, mates and avoiding predators and toxic environments. The mammalian peripheral olfactory system is located in the nasal cavity, where the vast majority of olfactory sensory neurons (OSNs) in the main olfactory epithelium (MOE) detect odorants and send sensory signals via axonal projection to the main olfactory bulb (MOB) in the brain for processing. Because the MOE is situated in the entrance of the respiratory passageway, inhaled airborne xenobiotics such as chemical irritants, toxicants and pollutants can damage MOE structure and function. Mechanisms for detecting xenobiotics in the MOE and protectively regulating olfactory activity are currently not well understood. Our lab previously identified a novel subpopulation of microvillous cells (MCs) in the MOE that express the transient receptor potential channel subfamily melastatin member 5 (TRPM5-MCs). Our subsequent studies characterizing TRPM5-MCs showed that they are cholinergic and chemoresponsive and capable of modulating the activities of neighboring OSNs and supporting cells, uncovering a novel intrinsic cholinergic network. However, the role of TRPM5-MCs in MOE maintenance under conditions of chemical challenge remains to be determined. In this dissertations, I have used immunohistochemistry and olfactory-guided behavior assays in transgenic and knockout mice to test the hypothesis that TRPM5-MCs regulate MOE chemosensation and protective maintenance in challenging chemical environments. My findings demonstrate that TRPM5-MCs maintain olfactory ability in guiding behavioral responses to food and social odor stimuli during two-week exposure to mild chemical irritants. Second, TRPM5-MCs are preferentially distributed in the anterior MOE and regulate region-specific changes in basal stem cell proliferation and tissue remodeling during chemical exposure, contributing to MOE functional maintenance. Lastly, I provide evidence that TRPM5-MC-dependent regional modification of the MOE during chemical exposure influences MOB morphology and activity downstream, leading to behavioral changes in odor discrimination and innate avoidance of aversive odor stimuli. This dissertations demonstrates that TRPM5-MCs regulate the adaptive morphological and functional maintenance of the MOE during chemical challenge.