Project Summary Unlike sight, taste and smell, mechanical senses extend beyond a single sensory organ, and encompass processes as diverse as hearing, touch, and interoception. Despite their physiological importance, the molecular identity of mechanotransduction channels has been mostly unknown. Our lab discovered the first vertebrate mechanically gated cation channels, PIEZO1 & 2, which are critical for many aspects of mechanosensation. We have shown that PIEZO2 plays a critical role in detecting touch, proprioception and lung stretch. Whether PIEZO ion channels play important roles in other forms of internal-organ mechanotransduction is not known. Stretch sensing in the stomach is known to contribute to satiety and downstream digestion processes, yet the molecular identity of stomach stretch sensors is unknown. Preliminary data suggests that stomach stretch-sensing neurons express PIEZO ion channels. This proposal will determine how PIEZO ion channels contribute to stomach mechanosensing, and importantly, define how stretch signals from the stomach impact feeding behavior and downstream physiology. Interoceptive processes rely on monitoring a combination of chemical and mechanical stimuli. Parsing the precise role of mechanotransduction in these systems is difficult without a molecular handle. For example, the role of mechanosensation in breathing was not defined until PIEZO2 deficiency was analyzed. The exact contribution of mechanical signals to eating is undefined and similarly complicated, but could have important consequences for understanding feeding circuits, weight gain, and metabolic disease. This is the first step to enable the study of how mechanical forces are encoded in the CNS to impact diverse physiological systems.