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.