The Impact of High Fat Diet on Brainstem Vagal Regulation

摘要： 目前对心脏副交感神经（或迷走神经）活动的理解明确表明，迷走神经 心脏迷走神经活动和心脏迷走神经活动中的稳态反射变化由心脏迷走神经运动介导 脑干中的神经元（CVNs）。因此，CVN在正常心血管功能中起着至关重要的作用。 尽管我们了解健康中的CVN神经生理学，但疾病中CVN功能障碍的可能性仍然存在。 目前仍不清楚.我们对认知和认知之间复杂的相互作用的理解尤其如此， 心血管功能心血管疾病风险的一个独特标志是低心脏迷走神经信号传导， 这种不平衡的程度与阿尔茨海默病（AD）风险的增加密切相关， 与之相关的痴呆症我们实验室的初步数据表明，迷走神经对心脏组织的活动， 减少，负责这种调节的迷走神经运动神经元在疾病晚期丢失。我们 指导这一建议的总体假设是，CVN活动减退导致心血管迷走神经张力差， 反射反应这种低活性最终会导致细胞大量丢失和疾病进一步进展。 然而，关键问题仍然存在，包括CVN抑制的增加有多快，以及 神经元兴奋性的作用。因此，本建议将1）定量确定心脏起搏的时间 在AD的5XFAD小鼠模型中的迷走神经信号传导，和2）建立CVN在早期心脏传导效应中的作用。 迷走神经信号。这些实验的预期结果将提供基本细节， 我们对心脏迷走神经调节和迷走神经调节心率的机制的理解。 确定迷走神经活动的早期机械后果可能会导致生物标志物的发现， 针对疾病机制而非症状的新疗法的早期测试。

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.