Cross-Modulation of Homeostatic Responses to Temperature, Oxygen and Carbon Dioxide in C. elegans

Different interoceptive systems must be integrated to ensure that multiple homeostatic insults evoke appropriate behavioral and physiological responses. Little is known about how this is achieved. Using C. elegans, we dissect cross-modulation between systems that monitor temperature, O₂ and CO₂. CO₂ is less aversive to animals acclimated to 15°C than those grown at 22°C. This difference requires the AFD neurons, which respond to both temperature and CO₂ changes. CO₂ evokes distinct AFD Ca²⁺ responses in animals acclimated at 15°C or 22°C. Mutants defective in synaptic transmission can reprogram AFD CO₂ responses according to temperature experience, suggesting reprogramming occurs cell autonomously. AFD is exquisitely sensitive to CO₂. Surprisingly, gradients of 0.01% CO₂/second evoke very different Ca²⁺ responses from gradients of 0.04% CO₂/second. Ambient O₂ provides further contextual modulation of CO₂ avoidance. At 21% O₂ tonic signalling from the O₂-sensing neuron URX inhibits CO₂ avoidance. This inhibition can be graded according to O₂ levels. In a natural wild isolate, a switch from 21% to 19% O₂ is sufficient to convert CO₂ from a neutral to an aversive cue. This sharp tuning is conferred partly by the neuroglobin GLB-5. The modulatory effects of O₂ on CO₂ avoidance involve the RIA interneurons, which are post-synaptic to URX and exhibit CO₂-evoked Ca²⁺ responses. Ambient O₂ and acclimation temperature act combinatorially to modulate CO₂ responsiveness. Our work highlights the integrated architecture of homeostatic responses in C. elegans.