PROJECT SUMMARY / ABSTRACT – Research Project Leader: Kathryn Schunke, PhD Diabetic Cardiomyopathy and Protection by Hypothalamic Parasympathetic Neuron Activation Cardiac autonomic neuropathy (CAN) is a serious complication of type 2 diabetes mellitus (T2DM) that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests as a decline in parasympathetic tone and overactivation of sympathetic activity than contributes to resting tachycardia and fixed heart rate, to development of myocardial infarction. Although it is a common complication, very little is known regarding how CAN directly increases the risk for myocardial injury and disease, and thus there are no current unified treatment algorithms other than life style changes, glycemic control and management of cardiovascular risk factors. We have recently identified a novel mechanism for restoring cardio-protective parasympathetic tone to the heart to reduce myocardial damage in diseases with similar autonomic dysfunction, such as heart failure, myocardial infarct and sleep apnea. Brainstem parasympathetic cardiac vagal neurons (CVNs) receive powerful excitation from a population of oxytocin (OXT) neurons that originate in the paraventricular nucleus of the hypothalamus (PVN). These unique neurons co-release OXT and enhance excitatory glutamatergic neurotransmission to CVNs. Based upon our novel results in diseases with similar autonomic imbalances, our overall hypothesis is that PVN OXT neuron activation will restore diminished parasympathetic activity and reverse the deleterious hypothalamic, brainstem and cardiac alterations that occur in an animal model of T2DM. This overarching hypothesis will be tested in two Specific Aims. Aim 1 will determine how T2DM alters cardiac function and autonomic tone, and determine if activation of PVN OXT neurons reverses these deleterious effects. In-vivo studies using telemetry instrumented rats will test the hypothesis that T2DM reduces cardiac function (quantified by echocardiography) and exercise tolerance, increases incidence of arrhythmia, and reduces heart rate recovery, and that PVN OXT stimulation will reverse these deleterious effects. Additional assessments of myocardial atherosclerosis, inflammation and fibrosis will probe potential mechanisms of loss-of-function and arrhythmogenesis. Insulin resistance, glucose tolerance and food intake will be assessed in parallel and correlated with disease progression and therapeutic regression. Aim 2 will characterize regulome underpinnings of T2DM mediated CAN by identifying the molecular phenotype of autonomic imbalance. We will test the hypothesis that T2DM alters gene expression of key pathways involved in maintaining mitochondrial metabolism, antioxidant defense, nitric oxide signaling, and neurotrophic growth in both PVN OXT neurons and CVNs, which can be reversed by PVN OXT activation. This will be accomplished using 10x Genomics Spatial Transcriptomic...