Inactivity and Enhanced Sympathoexcitation: Role of Neuroplasticity in the RVLM

描述(由申请人提供)：缺乏体力活动是心血管疾病(CVD)的主要独立风险因素，现在被认为是导致过早死亡的主要因素之一(Blair，2009)。随着治疗心血管疾病的医疗费用的增加，缺乏体力活动的比率继续上升。尽管有这些令人不安的趋势，但久坐不动的生活方式导致心血管疾病的机制尚不完全清楚。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)的脑干区域过度活动有关(Sve等人，2003；Guyenet，2006)。与体力活动相比，久坐不动的动物对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通过增加RVLM神经元的敏感性而促进CVD的发展。我们的长期目标是了解缺乏运动导致心血管疾病发展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。这项应用的总体目标是确定不运动(相对于运动)增加RVLM神经元交感输出的机制。中心假说是，在久坐动物身上观察到的交感兴奋增强是由于NMDA受体介导的RVLM神经元兴奋增加，该神经元调节参与血压调节的不同功能器官的交感活动。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这一应用的总体目标：1)确定久坐与身体活动条件对参与血压调节的不同目标器官的反射交感兴奋的改变程度。2)研究静坐状态与运动状态对RVLM脊髓投射交感兴奋神经元激活的影响。3)探讨NMDA受体介导的RVLM传递增强运动大鼠交感神经兴奋的机制。我们的建议提供了一个令人信服的理由来理解久坐不动的生活方式可能使个人容易患心血管疾病的机制。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。这项提议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有害影响，并确定治疗和预防心血管疾病的潜在治疗目标。这些研究可能通过以下方式改善不能或不愿锻炼的个人的生活：1)开发治疗心血管疾病的新方法；2)提高公众对久坐生活方式有害影响的认识；3)间接降低与缺乏运动有关的不断上升的医疗保健费用。 公共卫生相关性：拟议的研究与公共健康相关，因为久坐的生活方式是心血管疾病的主要风险因素，现在被认为是可预防的死亡的头号原因。这项建议研究了大脑中的一组重要神经元，我们认为这组神经元与久坐不动的人心血管疾病发病率增加有关。这一贡献意义重大，因为预计它将提供可用于制定治疗战略的知识，这些战略将抵消久坐不动的生活方式对心血管疾病的影响，这些疾病目前正在给人们和我们的卫生保健系统带来负担。

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because a sedentary lifestyle is a major risk factor for cardiovascular disease and is now considered the number one cause of preventable death. This proposal examines an important group of neurons within the brain that we propose contribute to the increased incidence of cardiovascular disease in sedentary individuals. This contribution is significant because it is expected to provide knowledge that could be used to develop therapeutic strategies that will counteract the effects of a sedentary lifestyle on cardiovascular diseases that are currently burdening the population and our health care system.