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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. <i>osm-8</i> mutants, which activate the osmotic stress response in the <i>C. elegans</i> skin, also exhibit defective osmotic avoidance behavior and an attenuated response of the ASH osmosensory neuron to hypertonic stimuli. Both <i>osm-8</i> and the Patched-related gene <i>ptr-23</i>, mutations in which suppress all <i>osm-8</i> phenotypes, function is the hypodermal lysosomes to regulate both physiology and behavior. Unbiased lipidomic analysis shows that <i>osm-8</i> leads to a <i>ptr-23</i>-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 <i>osm-8</i> 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 <i>vha-5</i>, 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.

在多细胞生物体内，神经系统向外周组织传递的信号可激活对应应激的生理应答。本研究证实，组织间的应激通讯亦可反向进行，即从外周组织传递至神经系统。osm-8突变体可在秀丽隐杆线虫（C. elegans）的表皮中激活渗透压应激应答，同时表现出渗透压规避行为缺陷，以及ASH渗透压感受神经元对高渗刺激的应答减弱。osm-8以及Patched相关基因ptr-23（其突变可抑制osm-8的所有表型）均在表皮溶酶体中发挥功能，同时调控生理状态与行为模式。无偏倚脂质组学分析显示，osm-8可引发依赖ptr-23的溶酶体特异性脂质双(单酰甘油)磷酸酯（bis(monoacylglycero)phosphate, BMP）水平升高，以及表皮溶酶体库的扩增。正如在表皮中敲除osm-8以遗传激活渗透压应激应答会引发Osm表型，急性生理暴露于渗透压应激同样会导致可逆的Osm表型。行为与遗传可塑性依赖甘油生物合成途径。但ptr-23仅参与osm-8诱导的行为可塑性调控，而非生理可塑性。与之相反，遗传与生理诱导产生的Osm表型均需要非典型的非神经元溶酶体V-ATP酶亚基vha-5，该亚基同样对生物体的渗透压应激存活至关重要。综上，本研究数据表明，表皮中应激信号的遗传或生理激活，可触发溶酶体相关信号，进而调控生物体生理状态以减弱感觉神经元回路的活动。此类“体-脑”内感受通讯或可帮助生物体更好地匹配神经元决策与整体生理状态。