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Contribution of neuroplasticity in the rostral ventrolateral medulla to physical inactivity-related cardiovascular disease

延髓头侧腹外侧神经可塑性对身体缺乏活动相关心血管疾病的贡献

基本信息

批准号：
10531897
负责人：
Patrick J Mueller
金额：
$ 62.55万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10531897
关键词：
Adverse effects Anatomy Animals Automobile Driving Blood Pressure Brain Brain Stem Brain region Brain-Derived Neurotrophic Factor COVID-19 pandemic Cardiovascular Diseases Cause of Death Cessation of life Clinical Clip DLG4 gene Data Development Dominant-Negative Mutation Economics Gene Targeting Glutamate Receptor Glutamates Goals Health Health Care Costs Healthcare Healthcare Systems Hypertension Incidence Individual Kidney Knowledge Label Laboratories Learning Link Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Manganese Mediating Memory Modeling Neuroanatomy Neuronal Plasticity Neurons Persons Phase Phenotype Physical activity Play Population Proteins Public Health Rattus Research Risk Factors Role Series Signal Transduction Smoking Stimulus Sympathetic Nervous System Synaptic plasticity Techniques Testing Therapeutic blood pressure regulation cardiovascular disorder risk cardiovascular risk factor clinically relevant glutamatergic signaling hypertensive in vivo innovation laser capture microdissection mRNA Expression multidisciplinary neurophysiology neurotransmission normotensive novel overexpression physical inactivity premature prevent protein expression receptor response sedentary sedentary lifestyle trend

项目摘要

Physical inactivity is a major independent risk factor for cardiovascular disease (CVD) and is now considered the leading cause of premature death (Blair, 2009). Rates of physical inactivity continue to increase along with health care costs to treat CVD. Despite these disturbing trends, the mechanisms by which a sedentary lifestyle leads to CVD are not fully known. CVD is associated with increased sympathetic nervous system activity and overactivity of a brainstem region known as the rostral ventrolateral medulla (RVLM) (Sved et al., 2003;Guyenet, 2006). Sympathoexcitatory responses to direct activation of the RVLM are enhanced in sedentary versus physically active animals (Mischel and Mueller, 2011) and are associated with changes in dendritic branching (Mischel et al., 2014). These data suggest that a sedentary lifestyle may contribute to the development of CVD by increased sensitivity of RVLM neurons. Our long term goal is to understand the central sympathetic mechanisms by which physical inactivity contributes to the development of CVD. This is an important clinical, economic and public health care problem. The overall objective of this application is to define the mechanisms by which physical inactivity increases, and physical activity prevents over-activation of presympathetic neurons in the RVLM. Our central hypothesis is that sedentary and hypertensive conditions each enhance glutamatergic signaling, initiate BDNF-dependent mechanisms and further propagate enhanced glutamatergic signaling; such that in combination, produce clinically relevant increases in sympathetic outflow and blood pressure. This project is expected to shift current paradigms regarding the mechanisms by which physical inactivity and pro-hypertensive stimuli combine to increase sympathetic activity and exaggerate the hypertensive phenotype. We will test our central hypothesis in distinct but interrelated aims using our well- established models of sedentary or active conditions and 2K-1C hypertension with sham-operated rats as controls. Aim 1: Utilize in vivo gene targeting to determine the contribution of BDNF-TrkB signaling in sedentary and 2K1C mediated neuroplasticity in the RVLM. Aim 2: Establish relationships between BDNF and synaptic plasticity-associated mRNA and protein expression in the RVLM of sedentary versus active, normotensive and 2K1C rats using laser capture microdissection of presympathetic RVLM neurons and tract-tracing, triple- immunofluorescent labeling. Aim 3: Quantify glutamatergic tone and neuronal activity in the RVLM of sedentary versus active, normotensive or 2K1C rats using magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) of the RVLM. Our studies combine state-of-the art techniques with conceptually innovative hypotheses to fill significant knowledge gaps towards understanding two fundamentally important and intertwined, yet unresolved health problems, i.e. physical inactivity and hypertension.

缺乏身体活动是心血管疾病（CVD）的一个主要独立危险因素，现在已被考虑在内