The Impact of High Fat Diet on Brainstem Vagal Regulation

高脂肪饮食对脑干迷走神经调节的影响

• 批准号: 10714645
• 负责人: CARIE Renee BOYCHUK
• 金额: $ 38.69万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714645
• 关键词: Acetylcholine; Administrative Supplement; Age Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Animals; Back; Basal Nucleus of Meynert; Biological; Brain Stem; Cardiac; Cardiovascular Physiology; Cardiovascular system; Cells; Central Nervous System; Cessation of life; Characteristics; Cognition; Complex; Data; Dementia; Dependence; Deposition; Development; Disease; Disease Progression; Early identification; Electrocardiogram; Electrophysiology (science); Fatty acid glycerol esters; Functional disorder; Ganglia; Generations; Genetic; Global Change; Health; Heart; Heart Rate; High Fat Diet; Impaired cognition; Injury; Laboratories; Measures; Mediating; Modeling; Molecular; Morbidity - disease rate; Motor Neurons; Motor output; Mus; Nervous System; Nervous System Physiology; Neuronal Dysfunction; Neurons; Nodal; Output; Pathogenesis; Pathologic; Pathology; Pharmacology; Physiology; Play; Production; Prognosis; Prosencephalon; Reflex action; Reflex control; Regulation; Rest; Risk; Role; Signal Transduction; Stroke; Symptoms; System; Tachycardia; Techniques; Telemetry; Testing; Time; Tissues; Tracer; Vascular Cognitive Impairment; Vascular Diseases; Viral; autonomic reflex; behavioral impairment; biomarker discovery; cardiovascular disorder risk; cholinergic; cholinergic neuron; cognitive function; experience; experimental study; knock-down; loss of function; mixed dementia; mortality; motor control; motor neuron function; mouse model; neuronal excitability; neurophysiology; neurotransmission; new therapeutic target; normal aging; novel; nucleus ambiguus; patch clamp; pharmacologic; prevent; response

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.

摘要： 目前对心脏副交感神经(或迷走神经)活动的理解明确地表明，迷走神经 心脏对心脏的活动和心脏迷走神经活动的稳态反射变化由心脏迷走神经运动介导 脑干的神经元(CVN)。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CVN在健康中的神经生理学，但在疾病中CVN功能障碍的可能性是 仍不清楚。这在我们理解认知和认知之间的复杂相互作用时尤其如此 心血管功能。心血管疾病风险的一个显著特征是低心脏迷走神经信号，以及 这种失衡的程度与患阿尔茨海默病(AD)的风险增加密切相关，并且 与之相关的痴呆症。我们实验室的初步数据显示，迷走神经对心脏组织的活动是 在疾病的晚期，负责这种调节的迷走运动神经元减少了。我们的 指导这一提议的总体假设是，CVN活动不足导致心血管迷走神经紧张性差和 反射反应。这种活动不足最终会导致强大的细胞丢失和进一步的疾病进展。 然而，关键问题仍然存在，包括增加对CVN的抑制的速度有多快以及发生了什么 神经元兴奋性确实起到了作用。因此，这项建议将1)定量地确定心脏手术的时间 迷走信号在5XFAD小鼠AD模型中的作用，以及2)CVN在早期心脏效应中的作用 这些小鼠的迷走神经信号。这些实验的预期结果将提供基本的细节 我们对心脏迷走神经调节的理解以及迷走神经调节心率的机制。 识别迷走神经活动的早期机制后果可能导致生物标志物的发现，以及 针对疾病机制而不是症状的新疗法的早期测试。