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

缺乏体力活动是心血管疾病(CVD)的主要独立危险因素，目前被认为 过早死亡的主要原因(布莱尔，2009年)。身体不活动的比率继续增加， 治疗心血管疾病的医疗费用。尽管有这些令人不安的趋势，久坐不动的生活方式 导致心血管疾病的原因尚不完全清楚。心血管疾病与交感神经系统活动增加和 被称为延髓头端腹外侧区(RVLM)的脑干区域的过度活动(Sve等， 2003年；Guyenet，2006年)。对直接激活RVLm的交感兴奋反应在 久坐的动物与体力活动的动物(Mischel和Mueller，2011)，并与 树突分枝(Mischel等人，2014年)。这些数据表明，久坐的生活方式可能有助于 RVLM神经元敏感性增加导致脑血管病的发生。我们的长期目标是理解中央 缺乏运动促进心血管疾病发展的交感神经机制。这是一个 重要的临床、经济和公共卫生保健问题。此应用程序的总体目标是定义 身体不活动增加的机制，以及身体活动防止过度激活 RVLM内的交感前神经元。我们的中心假设是久坐不动和高血压 每个都增强谷氨酸能信号，启动BDNF依赖机制，并进一步传播增强 谷氨酸能信号；这样，两者结合在一起，在临床上会导致交感神经流出增加 还有血压。该项目预计将改变目前关于以下机制的范例 缺乏体力活动和促高血压刺激相结合会增加交感神经活动并夸大 高血压表型。我们将在不同但相互关联的目标上测试我们的中心假设，使用我们的井- 以假手术大鼠为模型建立安静或活动状态及2K-1C高血压模型 控制。目的1：利用体内基因打靶技术研究BDNF-TrkB信号在久坐运动中的作用 2K1C介导RVLM的神经可塑性。目的2：建立脑源性神经营养因子与突触的关系 静息状态与活动状态、正常血压状态和正常血压状态下RVLM可塑性相关基因和蛋白的表达 2K1C大鼠用激光捕获显微切割交感前核神经元和束路示踪法，三重. 免疫荧光标记。目的3：定量测定久坐大鼠RVLM的谷氨酸能张力和神经元活动 与活动、正常血压或2K1C大鼠进行磁共振波谱(MRS)和磁共振成像 RVLM的磁共振成像(MRI)。我们的研究结合了最先进的技术和概念 创新假说填补了理解两个根本上重要的知识空白 以及相互交织但尚未解决的健康问题，即缺乏运动和高血压。

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.