All figures data 250903.xlsx

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 and an attenuated response of the ASH osmosensory neuron to hypertonic stimuli. Both osm-8 and the Patched-related gene ptr-23, mutations in which suppress all osm-8 phenotypes, function is the hypodermal lysosomes to regulate both physiology and behavior. 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 and genetic plasticity requires glycerol biosynthesis. However, ptr-23 is only required for osm-8 induced behavioral plasticity and not physiological plasticity. 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 organismal physiology to attenuate a sensory neuron circuit. Such ‘body-brain’ interoceptive communication may allow organisms to better match neuronal decision-making with organismal physiological state.