INS-17, an insulin-receptor ligand, confers specificity in adult IIS-regulated phenotypes in C. elegans

Insulin/IGF growth factor (IGF) signaling (IIS) is a pleiotropic signaling pathway that functions across tissues to coordinate phenotypic changes in response to nutrient status. Thus, the ubiquity of the IIS pathway hinders efforts to elucidate the mechanisms driving specific IIS-related phenotypes, Previous research in the nematode worm C. elegans has demonstrated that loss of function of the IGF transmembrane receptor (IR) ortholog, DAF-2, results in a doubled lifespan and enhanced learning and memory behaviors in young and aged animals. However, these findings are the result of reducing DAF-2 receptor function rather than modulating ligand-receptor interactions. In the current study, we aimed to dissect ligand-receptor interactions that may regulate associative behaviors apart from canonical IIS lifespan phenotypes in C. elegans. To this end, we performed targeted genetic screening of Insulin-like Peptides (ILPs) previously identified as DAF-2 antagonists to test their role in learning and memory phenotypes. We discovered that only a single uncharacterized ILP, INS-17, is required for learning and memory. We also demonstrate that INS-17 is sufficient to confer extended memory ability and can promote the maintenance of learning and memory with age. Additionally, we observe that ins-17 regulates learning and memory ability independent of lifespan, uncoupling IIS-mutant phenotypes. We find that regulation of the ins-17 genetic locus explains its unique requirement among ILP for learning and memory behaviors. Finally, we found that INS-17 may act to signal a state of nutrient deprivation that is required to properly process stimulus valence to promote advantageous behaviors. Our findings deepen the understanding of how IIS can regulate specific phenotypic outputs in response to changes in internal metabolic states.