The geometry and role of sequential activity in olfactory processing

Animals depend on their senses for survival. Mice, who rely on olfaction to navigate the world, can rapidly identify odors within a single sniff across a wide range of concentrations. In the mouse olfactory bulb (OB), mitral and tufted cells (MTCs) respond to odors by changing both the rate and timing of spikes relative to inhalation, resulting in reliable, odor specific sequences that evolve over a single sniff. However, it remains unknown how sequential MTC activity is organized. Specifically, what defines the order in which MTCs fire, and what information is encoded in these sequences? To address this, we performed 2-photon (2P) calcium imaging of hundreds of MTCs expressing the fast calcium indicator jGCaMP8f, permitting us to monitor the sub-sniff timing of responses to a battery of odors. We constructed a space of MTC tuning using the pairwise correlations between MTC odor responses averaged over a single sniff. We then analyzed the propagation of sequences in this space and discovered that sequences originated in a set of similarly tuned neurons and propagated to more distantly tuned neurons, so that the latency of MTC activation was linearly related to distance in tuning space. Analyzing the concentration dependence of sequence propagation, we found that the early part of the sequences carried information that was concentration invariant, while later MTC responses were inconsistent across concentrations. Finally, inspired by the discovery that similarly tuned MTCs are activated sequentially across odors, we constructed and analyzed a computational model for sequence-based unsupervised training of synapses from MTCs to the piriform cortex, which revealed that sequential activity across the entire sniff permits perceptual generalization for novel odors.