Enhanced Sympathoexcitation and Inactivity: Role of NMDA Neuroplasticity in RVLM

描述（由申请人提供）：缺乏身体活动是心血管疾病的主要风险因素，心血管疾病是美国的主要死亡原因。几种与不活动有关的心血管疾病，如肥胖和高血压，其特征在于血压升高和交感神经系统活动增加。交感神经系统主要由一个重要的大脑区域控制，称为延髓头端腹外侧（RVLM）。尽管在我们的社会中，身体不活动和心血管疾病的发生率越来越高，但人们对这个大脑区域如何随着时间的推移而变化知之甚少。缺乏对身体活动如何影响这一重要大脑区域而导致心血管疾病的了解，是我们领域的一个根本性空白。这项研究计划将研究在久坐与体力活动动物中RVLM对心血管系统的调节随时间发生的变化。来自申办方实验室的最新数据表明，相对于体力活动动物，久坐动物对RVLM激活的反应增强。RVLM的过度活动可能是许多心血管疾病中出现的交感神经系统活动总体升高的关键因素。该建议的中心假设是，身体不活动增强，而身体活动减少RVLM产生的交感神经激活。该中心假设基于申办方实验室的强有力的初步和已发表数据。这个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。该提案采用了一种实验设计，将检查久坐条件下发生的时间依赖性变化。活动动物将被视为“健康”对照，而久坐动物将被视为疾病模型。总的来说，这一建议解决了一个基本问题，即身体不活动对脑干调节交感神经系统活动的影响，是理解身体不活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.