The three components of the peripheral autonomic nervous system, the parasympathetic, sympathetic and sensory nerves, work together to prevent life-threatening fluctuations in glucose homeostasis. They do so in part by regulating hormone secretion from the pancreatic islet. Stimulating autonomic nerves with electrodes has recently been recognized as a potential way to treat diseases (neuromodulation). Given its central role in glucose metabolism and diabetes, the pancreatic islet is considered a primary target for neuromodulation. To propose electrical stimulation of nerves to treat diabetes, however, it is essential to understand how islet nerves impact insulin secretion from the beta cell. The objective of this application is to determine the mechanisms nerves use to control hormone secretion from the pancreas. Recent anatomical studies show in detail how autonomic nerves innervate the islet, but how exactly autonomic nerves impact hormone secretion from the islet is not known. We hypothesize that parasympathetic, enteric, and sensory neural pathways act through intrapancreatic ganglia to modulate local cholinergic control of islet cell function. The rationale for the proposed research is that there is a need to understand the local mechanisms of autonomic nerve control of hormone secretion from the islet, which is relevant to the mission of the NIH. Guided by preliminary data, our hypothesis will be tested by pursuing two specific aims: (1) the role of pancreas sensory innervation in regulating islet function, and (2) the role of the intrapancreatic ganglion as a signaling hub controlling islet function. Under the first aim, we will test that the vagal sensory innervation of the islet participates in a vagovagal neuronal circuit regulating islet hormone secretion. We will selectively stimulate islet cells with a chemogenetic approach and gain genetic access to activated neurons with the Targeted Recombination in Active Populations (TRAP) system. We will combine TRAP with tools for labeling, tracing, recording, and manipulating neurons in the brainstem activated by islet cell stimulation. Under the second aim, we will test that intrapancreatic ganglia integrate signals from parasympathetic efferent nerves, enteric neurons, and sensory axons to compute an executive summary of gut and brain inputs to adjust the local cholinergic control they exert on islet cells. We will stimulate parasympathetic, enteric and sensory innervation of the ganglion ex vivo and in vivo with chemogenetic and optogenetic tools and measure the effects in intrapancreatic neurons. We will further study how manipulating intrapancreatic neuronal activity affects islet function and glucose metabolism (insulin plasma levels and glycemia). We expect that applying our novel approaches to measure and manipulate pancreas nerve activity will yield important information about how nerves affect islet biology. This contribution is significant because it will provide fundamental knowle...