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.

抽象的： 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 心脏的活动和心脏迷走神经活动的稳态反射变化是由心脏迷走神经运动介导的 脑干中的神经元（CVN）因此，CVN 在正常心血管功能中发挥着重要作用。 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。 对于我们对认知与认知之间复杂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显着特征是心脏迷走神经信号传导低下，以及 这种不平衡的程度与患阿尔茨海默病 (AD) 的风险增加密切相关，并且 我们实验室的初步数据表明，迷走神经活动对心脏组织有影响。 减少，并且负责这种调节的迷走神经运动神经元在疾病晚期会消失。 指导这一提议的总体假设是 CVN 活性低下会导致心血管迷走神经紧张，并且 这种反射反应的减退最终会导致大量的细胞损失和进一步的疾病进展。 然而，关键问题仍然存在，包括 CVN 的抑制作用增加发生的速度有多快以及什么 因此，该提案将1）定量地确定心脏起搏的时间。 AD 5XFAD 小鼠模型中的迷走神经信号传导，以及 2) 确定 CVN 在早期心脏病影响中的作用 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负责迷走心率调节的机制的理解。 识别迷走神经活动的早期机制后果可能会导致生物标志物的发现，并且 针对疾病机制而非症状的新疗法的早期测试。