Hypothalamic and Limbic Forebrain Stress Reactivity

描述（由申请人提供）：在对急性应激源的反应中，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，这支持适应性应激反应（即“战斗或逃跑”）。然而，一些个体对急性心理压力源表现出“夸张的”心血管反应（例如，压力源引起的血压大变化）。这些人患冠心病的风险更大，这是上个世纪美国人死亡的主要原因。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，投射到神经节前神经元，最终支配身体器官。下丘脑室旁核（PVN）在控制应激反应中尤为重要，因为它不仅控制对应激的自主反应，还控制应激源诱发的激素释放。动物文献表明，PVN的活动受皮层和边缘区域的调节，这些区域也参与心血管功能的调节，特别是前额叶皮层（PFC）和终纹床核（BNST）。此外，动物文献表明，PFC通过投射到BNST对PVN施加抑制影响，BNST通过直接、密集的投射激活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。我们的目的是利用功能磁共振成像（fMRI）技术研究亚属扣带皮层（SCC，大鼠内侧PFC的人类同源物）、BNST和PVN在人类心血管应激反应中的作用。因此，我们假设心血管应激反应的个体差异将与scc - bst - pvn回路的相应个体差异相关。特异性目的1验证了心血管应激反应性的个体差异与应激源诱发的SCC、BNST和PVN激活相关的假设。压力诱发的血压和心率变化将用于评估心血管应激反应。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。特异性目标2验证了心血管应激反应性的个体差异与这些区域之间的功能连通性相关的假设。功能连接分析测量不同大脑区域的相关激活，是人类大脑成像中检查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。

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.