Body-to-brain Insulin and Notch signaling regulates memory through neuronal CREB activity

While we think of memory regulation as autonomous to neurons, factors outside the brain can also affect neuronal function. In C. elegans , the insulin/IGF-1-like signaling (IIS) pathway regulates longevity ¹ , metabolism ^2,3 , and memory ^4,5 : long-lived daf-2 insulin/IGF-1 receptor mutants more than double memory duration after a single training session. It was assumed that this regulation was strictly neuronal, but we discovered that degradation of DAF-2 in the hypodermis also greatly extends memory via expression of the diffusible Notch ligand, OSM-11, which in turn activates Notch signaling in neurons. Single-nucleus RNA-sequencing of neurons revealed activation of CREB memory genes and CREB itself. Finally, we found that activation of the hypodermal IIS/Notch/CREB pathway as well as OSM-11 overexpression in aged animals rescues both learning and memory. Thus, insulin signaling in the liver-like hypodermis ⁶ non-autonomously regulates neuronal function, providing a systemic connection between metabolism and memory through IIS/Notch/CREB signaling from the body to the brain.