Hypothalamic and Limbic Forebrain Stress Reactivity

点击翻译按钮获取中文摘要

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.