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)的一个主要独立风险因素，现在被认为是过早死亡的主要原因(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，久坐不动的动物对直接激活RVLM的交感兴奋反应增强(Mischel和Mueller，2011)。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身体不活动增加的机制和时间进程，以及身体活动防止RVLM中的交感前神经元过度激活。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调节交感活动的RVLM神经元的结构和功能可塑性所致。我们将通过以下不同的、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吻区神经元活动的功能机制。2)确定静坐状态增强RVLm吻侧区域球脊髓神经元激活的结构机制。3)阐明了久坐状态导致RVLM吻区内源性兴奋性神经传递增强的分子和细胞机制。我们的建议提供了一个令人信服的理由来理解基本的分子、细胞和解剖学机制，通过这些机制，身体缺乏活动改变了RVLM的神经传递。如果没有这方面的知识，我们对缺乏运动如何增加心血管疾病发病率以及运动如何预防或挽救缺乏运动表型的理解是极其有限的。这一问题具有重大的社会和经济意义，因为缺乏运动被描述为“21世纪最大的卫生保健问题”(布莱尔，2009)。我们希望在这个为期五年的项目结束时确定体力活动和不活动对大脑区域的调节的影响程度，该区域对NORML和交感神经系统活动的病理生理学增加至关重要。这些研究可能会改善那些无法运动或发现运动困难的人的生活：1) 为心血管疾病开发新的治疗方案；2)提高公众对久坐生活方式有害影响的认识；3)间接降低与缺乏运动相关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 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.