Mitochondrial calcium modulates odor-mediated behavioral plasticity in Caenorhabditis elegans

Despite growing understanding of the various roles mitochondria play in neurons, how they contribute to higher brain functions such as learning and memory remains underexplored. Here, using the nematode Caenorhabditis elegans, we found that the mitochondrial calcium uniporter (MCU) pore-forming unit MCU-1 is required for aversive learning of specific odors sensed by the AWC sensory neuron. MCU-1 expression was required in the sensory neuron at the time of odor conditioning for proper behavioral response to 60 min of prolonged odor exposure. We discovered that calcium entry into the mitochondria in AWC responds to the length of odor stimulus: calcium is elevated after 60 minutes of odor but not after 30 minutes, suggesting a gating mechanism that can discriminate the duration of sensory stimuli. Through genetic and pharmacological manipulation, we show that calcium influx through the MCU causes mtROS production, leading to NLP-1 secretion from the AWC neuron and odor learning. Overall, our results demonstrate that, by regulating mitochondrial calcium entry, mitochondria can respond to the length of a sensory stimulus to modulate the synaptic response, resulting in context-appropriate learning and behavior.