Structural basis of CO2 valence coding in Drosophila

In the olfactory system, glomerular sensory channels of single receptor identity support reliable odor recognition for appropriate approach or avoidance behaviors. For many olfactory stimuli, the assigned sensory value is innate but modulated by the internal state and previous experiences. How context-dependent modulation of innate valence coding supports distinct behavioral responses is poorly understood. Here we show that CO2 sensory information in Drosophila, intrinsically aversive but modified by attractive food signals, diverges from the canonical glomerular channel already in the antennal lobe and is relayed via the polarized local interneuron LN23. LN23 relays sensory input via an extraglomerular CO2 pathway and manipulation of LN23 activity revealed a dominant role in CO2-induced avoidance behavior. The extraglomerular CO2 pathway projects to the posterior lateral protocerebrum (PLP) adjacent to the canonical Lateral Horn (LH) olfactory processing center and segregates into anatomically distinct valence channels. Connectome data together with functional characterization showed the convergence of parallel CO2 channels onto two interconnected third-order neurons. These neurons integrate additional sensory modalities via distinct mechanisms: while the glomerular CO2 pathway converges with food relay neurons onto separated dendritic domains of the PD5 interneuron in the LH, the extraglomerular pathways integrating CO2 information with antennal humidity and temperature modalities establish antagonistic inputs onto the PLP interneuron PV9. This early anatomical divergence of a defined olfactory channel followed by separated multi-modal integration provides a structural basis for context-dependent valence coding and appropriate behavioral responses.