The Impact of High Fat Diet on Brainstem Vagal Regulation

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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 cognition and cardiovascular function. A distinctive hallmark of cardiovascular disease risk is low cardiac vagal signaling, and the extend of this imbalance correlates strongly with increasing risk of developing Alzheimer’s Disease (AD), and its related dementias. Preliminary data from our laboratory demonstrate that vagal activity to cardiac tissue is reduced and that the vagal motor neurons responsible for this regulation are loss at late stages of disease. Our overall hypothesis guiding this proposal is that CVN hypoactivity drives poor cardiovascular vagal tonus and reflex responses. This hypoactivity will eventually lead to robust cell loss and further disease progression. However, critical questions remain, including how quickly does the increased inhibition of CVNs occur and what role does neuronal excitability play. Therefore, this proposal will 1) quantitively determine the timing of cardiac vagal signaling in the 5XFAD mouse model of AD, and 2) establish the role of CVNs in the effects of early cardiac vagal signaling in these mice. 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 vagal activity could lead to the discovery of biomarkers, and early testing of new therapeutics targeting disease mechanisms, rather than symptoms.