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.

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