Rapid nasal metabolism organizes the neural representation of odors

The olfactory system translates chemical stimuli (odorants) into neural patterns of activity that give rise to odor perception. Canonical models of odor coding consider the binding of odorants to receptors expressed on olfactory sensory neurons (OSNs) as the primary organizing step in this process 1. However, such models fail to account for key aspects of odorant-evoked responses measured in vivo. Here, we considered how a process peripheral to receptor-ligand binding - the metabolism of odorants by xenobiotic enzymes in the nasal mucosa - may impact odor codes in vivo. Using imaging in awake mice and odorants linked by well-characterized enzymatic pathways 2-4, we find that nasal metabolism rapidly generates odorous metabolites and profoundly alters odor representations over a time-scale relevant for odor perception. Rapid odorant metabolism explains what otherwise appears to be complex tuning of OSNs as well as diverse temporal response patterns not accounted for by a simple receptor-ligand model. While nasal metabolism introduces confusion between identity-based representations of inhaled versus metabolism-generated odorants, we find that inhalation-linked response timing resolves this confusion and that temporally segregated representations of inhaled versus metabolism-generated odorants are preserved at the level of olfactory bulb projections to cortex. These findings demonstrate that odorant metabolism is integral to olfactory sensation and define a novel role for timing in olfaction: to distinguish external chemical signals from those generated internally, potentially supporting distinct percepts and behavioral responses to each.