Insulin/IGF signaling regulates presynaptic glutamate release in aversive olfactory learning

Information flow through neural circuits is continuously modified by context-dependent learning. In the nematode Caenorhabditis elegans, pairing specific odors with food deprivation results in aversion to the odor. Here we identify cell-specific mechanisms of insulin/IGF receptor signaling that integrate sensory information with food context during aversive olfactory learning. Using a conditional allele of the insulin/IGF receptor DAF-2, we show that aversive learning to butanone, an odor sensed only by the AWCON olfactory neuron, requires DAF-2 in AWCON. Learning requires an axonally-localized DAF-2c isoform and the insulin receptor substrate (IRS) protein IST-1, but is partly independent of the FoxO transcription factor DAF-16. Upon food deprivation, the unconditioned stimulus for learning, DAF-2 expression increases post-transcriptionally through an insulin- and ist-1- dependent process. Aversive learning suppresses odor-regulated glutamate release from AWCON in wild-type animals but not in ist-1 mutants, suggesting that localized insulin signaling drives presynaptic depression to generate an aversive memory. ### Competing Interest Statement D.C. is the owner of iDu Optics LLC, a company that manufactures the LabCam device used in microscopy imaging, including C. elegans research. LabCam was not used in this study.