Traumatic injuries, major surgery, burns, cerebral ischemia and head injury can induce failure of glucose homeostasis characterized by hypercatabolism and severe hyperglycemia (HG). A thousand papers published over nearly a century reinforce the axiomatic relationship between trauma and HG. The HG of trauma is highly correlated with a poor chance of survival. Post trauma HG, aside from wreaking havoc with attempts to manage metabolic fuel reserves following a severe injury, exacerbates thrombogenesis, infection and inflammatory processes all of which increase morbidity and mortality. While the connection between trauma and metabolic failure characterized by HG is well accepted, there is no practical understanding of the mechanism relating disparate traumatic incidents with autonomic failure characterized by HG, beyond citing stress-related increases in sympathetic activation. This R21 proposal will test a preliminary hypothesis that thrombin (generated by bleeding trauma) and the activation of proteinase activated receptors (PARs) on astrocytes in the hindbrain can induce a sympathetically-mediated hyperglycemia. We further propose that gliotransmission from PAR-activated astrocytes in the hindbrain activates neurons in the solitary nucleus or basal lateral medulla. Neurons in these sites are critical to generating autonomic counter-regulatory responses characterized by the elevation of plasma glucose in reaction to low CNS glucose availability. This hypothesis is an extension of our earlier published results which have demonstrated that the severe gastric stasis following traumatic injury is likely due to the proteinase activation of PAR-expressing hindbrain astrocytes that then cause a cessation gastric motility via action on vagal regulatory circuits controlling the gut. The first im will combine neuronal labeling procedures to pre-identify neurons in the hindbrain known to be essential to sympathetically-mediated hyperglycemia with brain splice live cell calcium imaging methods. This technique will allow us to determine if PAR-activated astrocytes (i.e., that produce calcium spikes which drive gliotransmission) specifically activate these pre-identified neurons. The second aim will use site specific nano-injection combined with in vivo physiological techniques to study the effects of PAR agonists, localized cytoglucopenia, astrocyte blockade and sympathetic pathway blockade to determine the relevance of thrombin/PAR activation to glycemia. Revealing an interaction between injury (and PAR activation) and glucose sensing circuits in the hindbrain may produce new insights into the management of trauma-induced metabolic failure.