Project Summary The gut-brain axis, and in particular brain-stomach communication, are implicated in emotional and cognitive processing and often linked to many nervous system disorders, including psychosocial dysfunction, substance abuse, neurological diseases, and degeneration. While a large body of work exists on stomach-brain vagal pathways, much less is known about how the brain and the stomach may communicate through the spinal sensory pathways. This R01 application proposes to determine the anatomy, function, and circuitry targeted by gut-innervating spinal sensory ganglia. The proposed studies will test the overarching hypothesis that, similarly to musculoskeletal proprioception, gastrointestinal (GI) mechanical stimuli are signaled to the brain, specifically the lateral reticular nucleus (LRN), via shared spinal sensory pathways. In addition, the proposal will determine the functional impact of the gastric-spinal-brain pathways on brain functions including reward behaviors and brain circuitries including the parietal, insular, and orbitofrontal cortices. To address our aims, state-of-the-art methodology will be used including organ-specific targeting by combinatorial viral injection, optogenetics including optically guided, in vivo electrophysiology in awake mice, computer-operated intraluminal balloon distension, and whole-brain c-Fos maps using light-sheet microscopy. Our studies may reveal novel peripheral therapeutical targets for emotional and psychosocial disorders associated with abnormal gut-brain communication. Moreover, the neural circuitries to be described in our studies may also be targeted to alleviate abnormal psychological states, including the nausea, anorexia, and chronic fatigue typical of GI motility disorders.