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）的一个主要独立危险因素，现在被认为是过早死亡的主要原因之一（Blair，2009）。随着治疗心血管疾病的医疗费用不断增加，缺乏身体活动的比例也在不断增加。尽管存在这些令人不安的趋势，但久坐的生活方式导致心血管疾病的机制尚不完全清楚。 CVD与交感神经系统活动增加和被称为延髓头端腹外侧区（RVLM）的脑干区域过度活动有关（Sved等人，2003年；Guyenet，2006年）。与身体活跃的动物相比，久坐的动物对直接激活 RVLM 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会增加 RVLM 神经元的敏感性，从而导致 CVD 的发生。我们的长期目标是了解身体不活动导致心血管疾病发生的中枢交感神经机制。这是一个重要的临床、经济和公共卫生保健问题。该应用的总体目标是确定身体不活动（相对于身体活动）增加 RVLM 神经元交感神经输出的机制。核心假设是，在久坐动物中观察到的交感神经兴奋增强是由于 NMDA 受体介导的 RVLM 神经元兴奋增加所致，RVLM 神经元调节交感神经活动，以影响参与血压调节的不同功能器官。我们计划通过追求以下具体目标来测试我们的中心假设并实现本应用的总体目标：1）确定久坐与体力活动条件在多大程度上改变对参与血压调节的功能不同目标器官的反射性交感神经兴奋。 2) 检查久坐与体力活动条件对 RVLM 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 传输可能增强久坐大鼠与体力活动大鼠交感神经兴奋的机制。我们的建议提供了令人信服的理由来理解久坐的生活方式可能使个体易患心血管疾病的机制。我们期望在这个五年项目结束时确定身体不活动对一组神经元调节的影响程度，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。该提案的结果将有助于更好地了解久坐生活方式对心血管健康的不利影响，并确定治疗和预防 CVD 的潜在治疗目标。这些研究可能会通过以下方式改善那些无法或不愿意锻炼的人的生活：1）开发新的 CVD 治疗方案； 2）提高公众对久坐生活方式有害影响的认识； 3) 间接减少因缺乏身体活动而导致的不断上升的医疗费用。

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.