Signaling from the C. elegans Hypodermis Non-autonomously Facilitates Short-term Associative Memory

Memory loss is one of the most debilitating symptoms of aging. While we normally think of memory regulation as autonomous to the brain, other factors outside of the brain can also affect neuron function. We have shown that the longevity insulin/IGF-1 signaling (IIS) pathway regulates neuron-specific activity, but whether the maintenance of memory through the IIS pathway is completely autonomous to the nervous system, or if there are systemic inputs, is unknown. We address this question using the auxin-inducible degradation (AID) system to degrade the IIS receptor, DAF-2, in specific tissues. Surprisingly, DAF-2 degradation specifically in the hypodermis improves memory in both young and aged C. elegans through the hypodermal expression of the diffusible Notch ligand, OSM-11. The Notch receptor LIN-12 is required for OSM-11’s effect on memory, as are the downstream transcription factor LAG-1 and co-activator SEL-8. Furthermore, mid-life overexpression of the Notch ligand OSM-11 improves memory and slows cognitive decline. Hypodermal DAF-2 degradation suppresses the expression of ins-19 , whose downregulation extends memory. Together, our data suggest a model in which the hypodermis, a metabolic tissue, can non-autonomously regulate neuronal activity and function, indicating a systemic connection between metabolism and memory regulation.