Witrado, J.; Gundrum, E.; Veroli, M. V.; Mullett, S. J.; Gelhaus, S. L.; Lamitina, T.

In multicellular organisms, signaling from the nervous system to the peripheral tissues can activate physiological responses to stress. Here, we show that inter-tissue stress communication can also function in reverse, i.e. from the peripheral tissue to the nervous system. osm-8 mutants, which activate the osmotic stress response in the C. elegans skin, also exhibit defective osmotic avoidance behavior, which is regulated by the ASH neuronal avoidance circuit. osm-8 osmotic avoidance behavior is completely suppressed by mutation of the Patched/NPC1 homolog ptr-23 . The function of osm-8 and ptr-23 in the hypodermal epithelial cells is both necessary and sufficient for directing neuronal osmotic avoidance behavior. Endogenously tagged alleles of osm-8 and ptr-23 co-localize exclusively in the hypodermal lysosomes. Unbiased lipidomic analysis shows that osm-8 leads to a ptr-23 -dependent elevation of the lysosome specific lipid bis(monoacylglycero)phosphate (BMP) and expansion of the pool of hypodermal lysosomes. Just as genetic activation of the osmotic stress response by loss of osm-8 in the hypodermis causes an Osm phenotype, acute physiological exposure to osmotic stress also confers a reversible Osm phenotype. Behavioral plasticity requires glycerol production, as mutations in the glycerol biosynthetic enzymes gpdh-1 and gpdh-2 are defective in acquired Osm behavior. While the osm-8 induced Osm behavior requires ptr-23 , physiologically induced Osm behavior does not. Instead, both genetic and physiologically induced Osm phenotypes require the unusual non-neuronal lysosomal V-ATPase subunit vha-5 , which is also critical for organismal osmotic stress survival. Together, these data reveal that genetic or physiological activation of stress signaling from the skin elicits lysosome-associated signals that modulate the function of a sensory neuron circuit. Such body-brain interoceptive communication may allow organisms to better match neuronal decision-making with organismal physiological state.