ABSTRACT: Current understanding of cardiac parasympathetic (or vagal) activity unequivocally demonstrates that the vagal activity to the heart and homeostatic reflex changes in cardiac vagal activity are mediated by cardiac vagal motor neurons (CVNs) in the brainstem. Therefore, CVNs play an essential role in normal cardiovascular function. Despite our understanding of CVN neurophysiology in health, the potential for CVN dysfunction in diseases is still unclear. This is particularly true of our understanding of the complex interplay between diet and cardiovascular function. In some estimates, Americans are consuming 600 more calories from fat per day then any time in the recent past. This increased consumption of foods high in fat significantly elevated the risk of developing cardiovascular diseases. A distinctive hallmark of cardiovascular disease risk is low cardiac vagal signaling, and the extend of this imbalance correlates strongly with increasing risk morbidity and mortality. Preliminary data from our laboratory demonstrate that CVN activity is significantly reduced and inhibitory neurotransmission to CVNs is increased during early consumption of foods high in fat. This reduced CVN activity parallels a significant reduction in cardiac vagal contribution to resting heart rate. The reduction in vagal activity can be abolished through genetic knock down of a specific subunit of the receptors that mediate inhibition in CVNs. Critically, PKC inhibition also abolishes the influence of high fat diet on vagal function, and this increased PKCδ activity is likely mediated by increased activity of the alpha-1 adrenoreceptor on CVNs. Our overall hypothesis guiding this proposal is that high fat diet-induced increase in functional expression of inhibitory receptors in CVNs results in a progressive decline in overall vagal activity. However, critical questions remain, including how quickly does the increased inhibition of CVNs occur and what role does the PKCδ isoform play in this inhibition. Therefore, this proposal will 1) quantitively determine the timing of cardiac vagal signaling after high fat diet, and 2) establish the role of PKCδ in the effects of early HFD on CVN function. The anticipated results of these experiments will provide fundamental details in our understanding of cardiac vagal regulation and mechanisms responsible for vagal regulation of heart rate. Identifying the early mechanistic consequences of HFD on vagal activity could lead to the discovery of biomarkers, and early testing of new therapeutics targeting disease mechanisms, rather than symptoms.