Project Summary Although the integration of neurobiology into immunological research has just begun, it has already profoundly improved our understanding of immunology. By using the Caenorhabditis elegans model system, we have identified three specific neuro-immune regulatory circuits that are mediated by the G protein-coupled receptors OCTR-1, NPR-8, and NMUR-1, respectively. Our studies and others indicate that there could be a predetermined setpoint for internal immunity, like the setpoint for the human heart rate, and that the nervous system regulates immune responses to internal or external environmental changes and restores immune homeostasis by bringing immunity back to the setpoint. Considering this “setpoint for immune homeostasis” theory, we plan to investigate how the nervous system and immune system interact to achieve the resolution of infection and the specificity of innate immunity, two important but poorly understood issues in immunology. Previously, we have characterized the OCTR-1-dependent neuro-immune regulatory circuit in great detail and have revealed that NMUR-1 mediates the specificity of C. elegans innate immunity. Here, we propose studies to dissect the molecular and neuronal mechanisms underlying neural regulation of resolution in the context of the OCTR-1 circuit and to identify specific neurons, neural networks, and neural signals that regulate NMUR-1- mediated specificity of innate immunity. These studies will advance our understanding of how the nervous system controls both infection resolution and innate immune specificity as well as define key regulatory principles that govern neuro-immune relationships. Results from these studies could benefit the development of new treatments for infectious diseases and innate immune disorders.