Mechanisms of Odor Detection and Discrimination

Duke University, Durham NC

Investigators

Abstract

Project Summary A fundamental goal of sensory neuroscience is to understand how external signals from the environment are detected and translated into neural signals that underlie perception and enable discrimination of different stimuli. In the mammalian olfactory system, odorant detection and discrimination are mediated by hundreds of distinct odorant receptors (ORs) tuned to detect small, volatile molecules with diverse physicochemical properties. To understand the neural basis of olfactory sensation it is necessary to determine the nature of OR sensitivity and selectivity across olfactory chemical space, as well as how OR – odorant interactions drive neural activity. The proposed project addresses these goals by investigating OR selectivity and function at multiple levels for three ORs in the mouse olfactory system. The project builds on a well-established collaborative pipeline between the two co-Investigators that allows for predictions arising from structure-function studies and in vitro assays to be tested in vivo for the same ORs. The project is organized around two major Aims. Aim 1 will investigate the structural determinants of OR activation and corresponding neural signaling in awake, freely breathing mice. We will focus on three ORs – one Class I and two Class II ORs – where high-potency in vivo ligands and glomerular projection targets have already been identified and use OR-IRES- mKate2 gene knock-in mouse lines (already generated) crossed with lines expressing the latest- generation optical reporters (GCaMP8m) expressed in either olfactory sensory neurons or mitral/tufted cells. We will compare in vitro activation profiles and in vivo response features for each OR and test hypotheses for how OR activation translates to in vivo neural activity patterns at each level. Aim 2 will investigate the structural basis and in vivo efficacy of OR antagonism, which is hypothesized to shape the encoding and perception of odorant mixtures but is poorly understood. We will test a novel model of the structural basis for antagonism of an identified Class I OR using in vitro functional assays, then define the efficacy and specificity of OR antagonism in shaping odorant-evoked neural activity in the awake mouse. Completion of these Aims will provide new foundations for linking the understanding of olfactory sensing mechanisms from the level of ORs to the brain, pave the way for rational design of OR antagonists, and ultimately achieve a generalizable understanding of the relationship between OR structure, ligand selectivity, and OR-driven neural activity in vivo.