Insulin/IGF signaling regulates presynaptic glutamate release in aversive

Insulin/insulin-like growth factor (IGF) receptor signaling (IIS) supports context-dependent learning in verte-brates and invertebrates. Here, we identify cell-specific mechanisms of IIS that integrate sensory information with food context to drive synaptic plasticity and learning. In the nematode Caenorhabditis elegans, pairing food deprivation with an odor such as butanone suppresses attraction to that odor. We find that aversive ol-factory learning requires the insulin receptor substrate (IRS) protein IST-1 and atypical signaling through the insulin/IGF-1 receptor DAF-2. Cell-specific knockout and rescue demonstrate that DAF-2 acts in the AWC degrees N sensory neuron, which detects butanone, and that learning preferentially depends upon the axonally local-ized DAF-2c isoform. Acute food deprivation increases DAF-2 levels in AWC degrees N post-transcriptionally through an insulin-and insulin receptor substrate-1 (ist-1)-dependent process. Aversive learning alters the synaptic output of AWC degrees N by suppressing odor-regulated glutamate release in wild-type animals, but not in ist-1 mu-tants, suggesting that axonal insulin signaling regulates synaptic transmission to support aversive memory.