Integration of hydrogen peroxide sensing and detoxification by the C. elegans nervous system

Hydrogen peroxide (H₂O₂) is the most common reactive chemical threat organisms face. Here, we map the neural circuit that drives chemotactic escape from environmental H₂O₂ in the nematode C. elegans. Twenty-four neuron classes with sensory endings at the mouth and nose respond to H₂O₂, with dynamics encoding stimulus intensity and exposure history. Sensing begins when H₂O₂ oxidizes the peroxidatic and resolving cysteines of the cytosolic peroxiredoxin PRDX-2, which relays this oxidative signal to cysteines on the LITE-1 and GUR-3 ion channels, triggering calcium influx in sensory neurons that drive escape. Most of these neurons release glutamate to drive H₂O₂-dependent excitation of AIA interneurons, whereas others signal through non-glutamatergic routes. Thus, the C. elegans nervous system monitors H₂O₂-induced changes in the intracellular H₂O₂-detoxification machinery and relays them to interneurons driving organism-wide escape. This raises the possibility that changes in neuronal activity in aging and neurodegenerative diseases arise from altered peroxiredoxin-mediated H₂O₂ signaling rather than primarily from direct macromolecular damage by H₂O₂.