Inactivity and Enhanced Sympathoexcitation: Role of Neuroplasticity in the RVLM

描述（由申请人提供）：缺乏身体活动是心血管疾病（CVD）的主要独立风险因素，目前被认为是导致过早死亡的主要因素之一（Blair，2009）。身体不活动的比率继续沿着治疗心血管疾病的医疗保健费用的增加。尽管有这些令人不安的趋势，但久坐不动的生活方式导致CVD的机制尚不完全清楚。CVD与增加的交感神经系统活动和称为头端腹外侧髓质（RVLM）的脑干区域的过度活动有关（Sved等人，2003; Guyenet，2006）。与体力活动动物相比，久坐动物对RVLM直接激活的交感兴奋反应增强（Mueller，2007）。这些数据表明，久坐的生活方式可能有助于CVD的发展，通过增加RVLM神经元的敏感性。我们的长期目标是了解中枢交感神经系统的机制，通过这些机制，身体不活动有助于心血管疾病的发展。这是一个重要的临床、经济和公共卫生保健问题。本申请的总体目标是确定身体不活动（相对于身体活动）增加RVLM中神经元的交感神经输出的机制。中心假设是，在久坐的动物中观察到的增强的交感神经兴奋是由于增加NMDA受体介导的RVLM神经元的兴奋，其调节交感神经活性到参与血压调节的功能性不同器官。我们计划测试我们的中心假设，并通过追求以下具体目标来实现本申请的总体目标：1）确定久坐与身体活动条件改变反射交感神经兴奋到参与血压调节的功能不同的靶器官的程度。2)检查久坐与体力活动条件对RVLM的脊髓投射交感兴奋神经元激活的影响。3)确定NMDA受体介导的RVLM中的传递可能增强久坐与体力活动大鼠的交感兴奋的机制。我们的建议提供了一个令人信服的理由来理解久坐的生活方式可能使个人容易患上CVD的机制。我们希望在这个为期五年的项目结束时，确定身体不活动对一组神经元的调节的影响程度，这些神经元对交感神经系统活动的正常和病理生理增加至关重要。这项提案的结果将使人们更好地了解久坐不动的生活方式对心血管健康的不利影响，并确定治疗和预防心血管疾病的潜在治疗目标。这些研究可以通过以下方式改善无法或不愿锻炼的人的生活：1）开发CVD的新治疗方案; 2）提高公众对久坐不动生活方式的有害影响的认识; 3）间接减少与缺乏身体活动相关的不断上升的医疗保健费用。

DESCRIPTION (provided by applicant): Physical inactivity is a major independent risk factor for cardiovascular disease (CVD) and is now considered one of the leading contributors to 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 (Mueller, 2007). 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 determine mechanisms by which physical inactivity (versus physical activity) increases sympathetic output from neurons in the RVLM. The central hypothesis is that enhanced sympathoexcitation observed in sedentary animals is due to increased NMDA receptor-mediated excitation of RVLM neurons that regulate sympathetic activity to functional distinct organs involved in blood pressure regulation. We plan to test our central hypothesis and accomplish the overall objectives of this application by pursuing the following specific aims: 1) Determine the extent to which sedentary versus physically active conditions alter reflex sympathoexcitation to functionally distinct target organs involved in blood pressure regulation. 2) Examine the effect of sedentary versus physically active conditions on activation of spinally-projecting sympathoexcitatory neurons of the RVLM. 3) Ascertain the mechanisms by which NMDA receptor mediated transmission in the RVLM may enhance sympathoexcitation in sedentary versus physically active rats. Our proposal provides a compelling rationale to understand the mechanisms by which a sedentary lifestyle may predispose individuals to CVD. We expect to establish at the end of this five year project the extent to which physical inactivity impacts regulation of a group of neurons that are critical to normal and pathophysiological increases in sympathetic nervous system activity. The results of this proposal will provide a greater understanding of the detrimental effects of a sedentary lifestyle on cardiovascular health and define potential therapeutic targets for the treatment and prevention of CVD. These studies may improve the lives of individuals who are unable or unwilling to exercise by 1) the development of new treatment options for CVD; 2) increasing public awareness of the detrimental effects of a sedentary lifestyle; and 3) indirectly reducing escalating health care costs associated with physical inactivity.