Abstract Research during the last funding period of this NIGMS-funded MIRA award has significantly advanced understanding of the molecular immunobiology mechanisms at the interface between the nervous system and the immune system. As reported in a series of high impact publications, our lab’s discoveries of vagus nerve control of inflammation, termed “the inflammatory reflex,” the elucidation of the specific neural and molecular mechanisms, culminated in successful clinical trials in rheumatoid arthritis and Crohn’s disease. This NIGMS MIRA-supported work of basic immunobiology programs focuses on the anatomy, electrophysiology, and molecular mechanisms of the vagus nerve circuits controlling innate immunity. It is credited with establishing and leading the field of bioelectronic medicine. The present competing renewal proposes a logical, significant, innovative, and impactful continuation of this work delineating how the brain controls immunity. There remain many major unanswered questions. For example, what is the origin, anatomy, and function in the brain of neural signals that control inflammation? How does the brain sense and record the presence of inflammation in the body? And, what are the brain and nervous system mechanisms that stimulate inflammation? Some of these questions will be answered directly, and other new questions will likely arise during the course of work to guide additional exploration. The PI and his lab have assembled and lead teams to accomplish this work. They have the necessary experience and a track record in using optogenetics, transgenic, and knock-out mice, immunological disease models, imaging technologies, electro- and neuro-physiology methods, and basic immunology and neurobiology. They are in an ideal environment to successfully complete the proposed studies, both to advance the MIRA mission of NIGMS, and to continue their journey translating basic science into clinical investigation and practice.