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

• 批准号: 10344035
• 负责人: Patrick J Mueller
• 金额: $ 64.75万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10344035
• 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; Neuronal Plasticity; Neurons; Persons; Phase; Phenotype; Physical activity; Play; Population; Proteins; Public Health; Rattus; Research; Risk Factors; Role; Series; Signal Transduction; Stimulus; Sympathetic Nervous System; Synaptic plasticity; Techniques; Testing; Therapeutic; Time; blood pressure regulation; cardiovascular disorder risk; cardiovascular risk factor; clinically relevant; glutamatergic signaling; hypertensive; in vivo; innovation; laser capture microdissection; mRNA Expression; multidisciplinary; neurophysiology; normotensive; novel; overexpression; physical inactivity; premature; prevent; protein expression; receptor; response; sedentary; sedentary lifestyle; trend

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）的主要独立危险因素， 导致过早死亡的主要原因（Blair，2009）。身体不活动的比率继续沿着增加， 治疗CVD的医疗费用。尽管有这些令人不安的趋势， 导致CVD的原因尚不完全清楚。CVD与交感神经系统活动增加有关， 称为头端腹外侧髓质（RVLM）的脑干区域的过度活动（Sved等， 2003;Guyenet，2006）。对RVLM直接激活的交感兴奋性反应增强， 久坐与体力活动的动物（Mischel和Mueller，2011），并与 树枝状分支（Mischel等，2014年）。这些数据表明，久坐不动的生活方式可能有助于 通过增加RVLM神经元的敏感性发展CVD。我们的长期目标是了解中央 交感神经机制，身体不活动有助于心血管疾病的发展。这是一 重要临床、经济和公共卫生保健问题。本申请的总体目标是定义 身体不活动增加的机制，以及身体活动防止过度激活的机制 RVLM中的前交感神经元。我们的核心假设是久坐和高血压 每一个都增强了神经元能信号传导，启动BDNF依赖性机制，并进一步传播增强的 交感神经能信号传导;因此，在组合中，产生交感神经流出的临床相关增加 和血压。预计该项目将改变目前有关机制的范式， 身体不活动和促高血压刺激联合收割机增加交感神经活动， 高血压表型我们将测试我们的中心假设在不同的，但相互关联的目标，使用我们的良好- 以假手术大鼠为模型，建立安静或活动状态和2K-1C高血压模型， 对照目的1：利用体内基因打靶技术研究BDNF-TrkB信号通路在久坐不动脑损伤中的作用。 2K 1C介导的RVLM神经可塑性。目的2：建立BDNF与突触的关系 可塑性相关的mRNA和蛋白质表达的RVLM久坐与活跃，血压正常， 2K 1C大鼠使用激光捕获显微切割前交感RVLM神经元和束追踪，三重- 免疫荧光标记目的3：量化久坐者RVLM中的交感神经紧张和神经元活动 与活动、血压正常或2K 1C大鼠相比，使用磁共振波谱（MRS）和磁共振成像（MRI）， RVLM的核磁共振成像（MRI）。我们的研究结合了联合收割机最先进的技术和概念 创新的假设，以填补重大的知识差距，了解两个根本重要的 和相互交织但尚未解决的健康问题，即缺乏身体活动和高血压。