The brain and peripheral organs communicate through the peripheral nervous system (PNS) comprised of autonomic (sympathetic and parasympathetic) and sensory nerves. Pancreas is densely innervated by the PNS and their cell bodies reside in several ganglia, including nodose (NG), coeliac (CG) dorsal root ganglia (DRG) and intrapancreatic ganglia. Pancreatic innervation is altered in diabetes. Until now, we have lacked the ability to identify and specifically target pancreatic nerves and modulate their function to determine the physiological roles of pancreatic nerves. Here, we delivered retrograde tracers into the pancreas and quantified pancreas-projecting neurons in NG/DRG/CG with 3D visualization and tissue clearing. Next, we assessed the efficiency of different adeno-associated virus (AAV) serotypes, delivery routes and promoters to target construct expression in defined pancreatic nerves. Specific AAV serotypes selectively target pancreas-projecting efferent CG neurons or afferent NG neurons. We utilized Cre-dependent AAV to deliver activating chemogenetic constructs into pancreatic parasympathetic nerves. Targeted activation of the pancreatic parasympathetic neurons improved glucose tolerance and increased insulin secretion. Our studies demonstrate that specific AAV serotypes can target defined pancreatic innervation. Targeted modulation of pancreatic parasympathetic nerves can clarify crucial roles of peripheral nerves in pancreatic function and pathophysiology.
M. Jimenez Gonzalez: None. R. Li: None. L.E. Pomeranz: None. G.J. Schwartz: None. S. Stanley: None.
American Diabetes Association (1-17-ACE-31 to S.S.); National Institutes of Health (1R01NS097184, OT2OD024912); Alexander and Alexandrine Sinsheimer Scholar Award