Two insulin-like peptides antagonistically regulate aversive olfactory learning in C. elegans.

The insulin/insulin-like peptides (ILPs) regulate key events in physiology, including neural plasticity. However, the cellular and circuit mechanisms whereby ILPs regulate learning remain largely unknown. Here, we characterize two ILPs that play antagonistic roles in aversive olfactory learning of C. elegans. We show that the ILP ins-6 acts from ASI sensory neurons to enable learning by repressing the transcription of another ILP, ins-7, specifically in URX neurons. A high level of INS-7 from URX disrupts learning by antagonizing the insulin receptor-like homolog DAF-2 in the postsynaptic neurons RIA, which play an essential role in the neural circuit underlying olfactory learning. We also show that increasing URX-generated INS-7 and loss of INS-6, both of which abolish learning, alter RIA neuronal property. Together, our results reveal an "ILP-to-ILP" pathway that links environment-sensing neurons, ASI and URX, to the key neuron, RIA, of a network that underlies olfactory plasticity and modulates its activity.