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，目前被认为是过早死亡的主要原因（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性反应增强（Mischel和Mueller，2011）。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定义身体不活动增加的机制和时间过程，以及身体活动防止RVLM中的前交感神经元过度激活。中心假设是，增强交感神经兴奋在久坐不动的动物是由于结构和功能的神经可塑性RVLM神经元，调节交感神经活动。我们将通过关注以下不同的、相互关联的特定目标来检验这一中心假设：1）确定久坐条件增强RVLM吻侧区域神经元活动的功能机制。2)定义结构机制，久坐的条件下，增强激活的延髓脊髓神经元在嘴部地区的RVLM。3)描述分子和细胞机制，通过这些机制，久坐状态在RVLM的嘴侧区域产生增强的内源性兴奋性神经传递。我们的建议提供了一个令人信服的理由，了解潜在的分子，细胞和解剖机制，身体不活动改变RVLM的神经传递。如果没有这些知识，我们对缺乏身体活动如何增加心血管疾病的发病率以及运动如何预防或挽救缺乏活动表型的理解是非常有限的。这一问题具有重大的社会和经济影响，因为身体活动不足被描述为“21世纪世纪最大的健康问题”（Blair，2009）。我们希望在这个五年项目结束时确定身体活动和不活动对交感神经系统活动正常和病理生理增加至关重要的大脑区域的调节的影响程度。这些研究可能会改善那些无法锻炼或难以锻炼的人的生活， 开发心血管疾病的新治疗方案; 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 the leading cause of 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 (Mischel and Mueller, 2011). 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 define the mechanisms and time course by which physical inactivity increases, and physical activity prevents over-activation of presympathetic neurons in the RVLM. The central hypothesis is that enhanced sympathoexcitation observed in sedentary animals is due to structural and functional neuroplasticity in RVLM neurons that regulate sympathetic activity. We will test this central hypothesis by focusing on the following distinct, bt interrelated specific aims: 1) Determine the functional mechanisms by which sedentary conditions enhance neuronal activity in rostral regions of the RVLM. 2) Define structural mechanisms by which sedentary conditions enhance activation of bulbospinal neurons in rostral regions of the RVLM. 3) Delineate molecular and cellular mechanisms by which sedentary conditions produce enhanced endogenous excitatory neurotransmission in rostral regions of the RVLM. Our proposal provides a compelling rationale to understand the underlying molecular, cellular and anatomical mechanisms by which physical inactivity alters neurotransmission in the RVLM. Without this knowledge our understanding of how physical inactivity increases the incidence of cardiovascular disease and how exercise prevents or rescues the inactivity phenotype is extremely limited. This problem has significant social and economic implications since physical inactivity is described as "the biggest health care problem of the 21st century"(Blair, 2009). We expect to establish at the end of this five year project the extent to which physical activity and inactivity impact regulation of a brain region that is critical to norml and pathophysiological increases in sympathetic nervous system activity. These studies may improve the lives of individuals who are unable to exercise or find difficulty exercising 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.