Enhanced Sympathoexcitation and Inactivity: Role of NMDA Neuroplasticity in RVLM

描述（由申请人提供）：缺乏运动是心血管疾病的主要危险因素，在美国是导致死亡的主要原因。一些与不运动相关的心血管疾病，如肥胖和高血压，其特征是血压升高和交感神经系统的活动。交感神经系统主要由一个重要的大脑区域控制，称为吻侧腹外侧髓质（RVLM）。尽管在我们的社会中，缺乏运动和心血管疾病的发病率越来越高，但人们对经常运动的人和久坐不动的人的大脑区域随着时间的推移是如何变化的知之甚少。缺乏运动如何通过对这一重要大脑区域的影响而导致心血管疾病，这一知识的缺乏代表了我们这个领域的一个根本空白。这项研究计划将研究久坐与运动动物的RVLM对心血管系统的调节随时间的变化。赞助商实验室最近的数据表明，相对于体力活动的动物，久坐的动物对RVLM激活的反应更强。RVLM的过度活动可能是交感神经系统活动整体升高的关键因素，这在许多心血管疾病中都可以看到。该提议的中心假设是，不运动增强了RVLM产生的交感神经激活，而体育活动则降低了RVLM产生的交感神经激活。这一中心假设是基于赞助商实验室强有力的初步和已发表的数据。该项目将确定久坐不动的生活方式可能导致心血管疾病的中枢神经系统机制。本方案采用实验设计来检验久坐状态下发生的随时间变化。活动的动物将被认为是“健康”的对照，而久坐的动物将被认为是疾病模型。总的来说，这一建议解决了一个关于缺乏运动对脑干调节交感神经系统活动的影响的基本问题，是理解缺乏运动对心血管疾病的贡献的关键一步。

DESCRIPTION (provided by applicant): Physical inactivity is a major risk factor for cardiovascular disease, the leading cause of death in the United States. Several inactivity-related cardiovascular diseases such as obesity and hypertension are characterized by increased blood pressure and activity of the sympathetic nervous system. The sympathetic nervous system is primarily controlled by an important brain region known as the rostral ventrolateral medulla (RVLM). Despite increasing rates of physical inactivity and cardiovascular disease in our society, there is very little known about how this brain region changes over time in individuals that are physically active versus those that remain sedentary. This lack of knowledge about how physical inactivity may contribute to cardiovascular disease by effects on this important brain region represents a fundamental gap in our field. This research proposal will study the changes that occur over time in regulation of the cardiovascular system by the RVLM in sedentary versus physically active animals. Recent data from the Sponsor's laboratory has shown that the response to activation of the RVLM is enhanced in sedentary relative to physically active animals. Over activity of the RVLM could be a key contributor to the overall elevation in sympathetic nervous system activity that is seen in many cardiovascular diseases. The central hypothesis of this proposal is that physical inactivity enhances, and physical activity reduces sympathetic activation produced by the RVLM. This central hypothesis is based on strong preliminary and published data from the Sponsor's laboratory. This project will determine central nervous system mechanisms by which a sedentary lifestyle may contribute to cardiovascular disease. This proposal utilizes an experimental design that will examine time-dependent changes that occur under sedentary conditions. Active animals will be considered the "healthy" control, and sedentary animals the disease model. As a whole, this proposal addresses a fundamental question regarding the effect of physical inactivity on regulation of sympathetic nervous system activity by the brain stem and is a key step in understanding the contribution of physical inactivity to cardiovascular disease.