Hypothalamic and Limbic Forebrain Stress Reactivity

描述（由申请人提供）：响应于急性应激源，自主神经系统协调许多心血管调节，包括血压和心率的增加，其支持适应性应激反应（即，“战斗或逃跑”）。然而，有些人对急性心理应激源表现出"夸大"的心血管反应（例如，血压的大的应激物诱发的变化）。这些人患冠心病的风险更大，冠心病是上个世纪美国的主要死因。 大脑中的回路控制着对压力的自主反应。这些回路开始于下丘脑和边缘前脑区域，投射到节前神经元，最终支配身体器官。下丘脑室旁核（PVN）在控制应激反应中特别重要，因为它不仅控制对应激的自主反应，而且控制应激诱发的激素释放。动物文献表明，PVN活动是由皮质和边缘系统区域调节的，这些区域也参与调节心血管功能，特别是前额叶皮质（PFC）和终纹床核（BNST）。此外，动物文献表明，前额叶皮质通过向BNST的投射对PVN施加抑制影响，并且BNST通过直接、致密的投射激活PVN。这些区域共同形成一个功能回路，调节心血管对压力的反应。我们的目标是调查的作用，膝下扣带皮层（SCC，人类同系物的大鼠内侧PFC），BNST，PVN在人类心血管反应的压力，使用功能磁共振成像（fMRI）技术。因此，我们假设心血管应激反应的个体差异与SCC-BNST-PVN回路中相应的个体差异相关。具体目标1检验了心血管应激反应性的个体差异与应激诱发的SCC、BNST和PVN激活共变的假设。压力诱发的血压和心率变化将用于评估心血管压力反应性。我们感兴趣的区域的应激诱发激活将使用fMRI血氧水平依赖（BOLD）反应进行检查。具体目标2测试的假设，心血管应激反应的个体差异与这些区域之间的功能连接协变。功能连接分析测量不同大脑区域的相关激活，是检查人脑成像中电路系统的最佳技术。我们提出的实验将增强我们对冠心病潜在风险的神经回路的理解。 公共卫生相关性：冠心病（CHD）是上个世纪美国的主要死因。有些人对急性心理应激源表现出"夸大的"心血管反应（例如，血压变化大），这些人患冠心病的风险更大。因此，为了更好地了解CHD风险的神经机制，重要的是要了解控制心血管对压力反应的神经回路功能的个体差异。

DESCRIPTION (provided by applicant): In response to an acute stressor, the autonomic nervous system orchestrates a number of cardiovascular adjustments, including increases in blood pressure and heart rate, which support an adaptive stress response (i.e., "fight or flight"). However, some individuals display "exaggerated" cardiovascular reactions to acute psychological stressors (e.g., large stressor-evoked changes in blood pressure). These individuals are at greater risk for coronary heart disease, the leading cause of death in the United States for the last century. Circuits within the brain control autonomic responses to stress. These circuits begin in hypothalamic and limbic forebrain regions that project to preganglionic neurons that ultimately innervate body organs. The paraventricular nucleus of the hypothalamus (PVN) is particularly important in controlling stress responses in that it not only controls autonomic responses to stress, but also controls stressor-evoked hormone release. The animal literature demonstrates that PVN activity is modulated by cortical and limbic regions also involved in modulating cardiovascular function, particularly the prefrontal cortex (PFC) and the bed nucleus of the stria terminalis (BNST). Further, the animal literature has shown that the PFC exerts an inhibitory influence over the PVN via its projection to the BNST and that the BNST activates the PVN through a direct, dense projection. Together, these regions form a functional circuit that modulates cardiovascular responses to stress. Our goal is to investigate the role of the subgenual cingulate cortex (SCC, the human homologue of the rat medial PFC), BNST, and PVN in human cardiovascular responses to stress using functional magnetic resonance imaging (fMRI) techniques. Thus, we hypothesize that individual differences in cardiovascular stress reactivity will be associated with corresponding individual differences in the SCC-BNST-PVN circuit. Specific Aim 1 tests the hypothesis that individual differences in cardiovascular stress reactivity covary with stressor- evoked activation of the SCC, BNST, and PVN. Stressor-evoked changes in blood pressure and heart rate will be used to assess cardiovascular stress reactivity. Stressor-evoked activation of our regions of interest will be examined using fMRI blood oxygen level-dependent (BOLD) responses. Specific Aim 2 tests the hypothesis that individual differences in cardiovascular stress reactivity covary with functional connectivity between these regions. Functional connectivity analyses measure the correlated activation of distinct brain regions and are the best techniques available for examining a system of circuits in human brain imaging. Our proposed experiments will enhance our understanding of the neural circuitry underlying risk for coronary heart disease. PUBLIC HEALTH RELEVANCE: Coronary heart disease (CHD) has been the leading cause of death in the United States for the last century. Some individuals display "exaggerated" cardiovascular reactions to acute psychological stressors (e.g., large changes in blood pressure) and these individuals are at greater risk for developing CHD. Thus, to better understand neural mechanisms underlying CHD risk, it is important to understand individual differences in the function of neural circuits that control cardiovascular responses to stress.