Mutations in the guanylate cyclase gcy-28 neuronally dissociate naïve attraction and memory retrieval

The molecules and mechanisms that are involved in the acquisition, storage, and retrieval of memories in many organisms are unclear. To investigate these processes, we use the nematode worm Caenorhabditis elegans, which is attracted naïvely to the odorant benzaldehyde but learns to avoid it after paired exposure with starvation. Mutations in the receptor-like guanylate cyclase GCY-28 have previously been thought to result in a behavioral switch in the primary chemosensory neuron AWC^ON , from an attractive state to an aversive (already-learned) state. Here, we offer a different interpretation and show that GCY-28 functions in distinct neurons to modulate two independent processes: naïve attraction to AWC^ON -sensed odors in the AWC^ON neuron, and associative learning of benzaldehyde and starvation in the AIA interneurons. Consequently, mutants that lack gcy-28 do not approach AWC^ON -sensed odors and cannot associate benzaldehyde with starvation. We further show that this learning deficit lies in memory retrieval, not in its acquisition or storage, and that GCY-28 is required in AIA for sensory integration only when both AWC neurons (ON and OFF) are activated by chemical stimuli. Our results reveal a novel role of GCY-28 in the retrieval of associative memories and may have wide implications for the neural machineries of learning and memory in general.