Project Summary/Abstract Timely and precisely sensing signals inside the body is critical for survival. Through the vagus nerve, a major interoceptive system and a key body-brain axis, our brain is able to discriminate numerous physically diversified inputs from various visceral organs to generate appropriate physiological responses. Anatomical, neurochemical, and electrophysiological properties of vagal sensory neurons (VSNs) have been extensively investigated over the past several decades, and their genetic heterogeneity has been beautifully revealed recently. Despite these efforts in understanding individual vagal body-brain circuits, it is still unclear how this important interoceptive system is organized to precisely present all body signals. The molecular and functional architecture of the sensory vagus nerve remain to be a mystery. Are there unique features in VSNs innervating different visceral organs? How are different body signals coded by the vagus nerve? What are the anatomical and molecular basis for sensing similar/distinct inputs from different visceral organs? Here, we propose to bring knowledge and innovative technologies in neuroscience, physiology, genetics, and computational biology to this important interdisciplinary area to better understand the organization of this critical interoceptive system. Previously, we have developed a number of novel molecular and genetic techniques in the vagus nerve to enable high throughput analysis of neuronal identities based on anatomical structures and neuronal activities. Here we will employ these powerful tools to determine, through three specific aims, whether the vagus nerve uses specific genetic signatures to code visceral organs and forms modular anatomical and functional units for sensing diverse body signals. We expect that studies proposed here will reveal many important details for this essential interoceptive system. We believe the proposed project will provide not only a critical foundation for delineating the underlying sensory mechanisms but also genetic access for charting distinct body-to-brain neural circuits and precise modulation of autonomic functions. A comprehensive and systematic understanding of diverse body brain pathways will open up new vistas in this important area of interoception and may bring novel concepts and therapeutic targets into the field of neuroprotection.