Neural Circuitry Underlying Chronic Stress Effects

描述（由申请人提供）：以重大不良生活事件的形式长期暴露于压力与抑郁、焦虑和创伤后应激障碍和慢性疲劳综合征等疾病的发展有关。下丘脑-垂体-肾上腺（HPA）轴活动的变化是这些疾病的重要特征，可能反映了大脑回路的可塑性，该回路协调这些神经内分泌反应与行为和自主神经功能。经历慢性应激的动物表现出许多在患病个体中看到的神经内分泌、自主神经和行为变化。使用HPA活性作为我们的主要终点，我们已经确定了丘脑室旁核（pPVTh）的后分裂作为HPA反应的一个关键介质在慢性应激大鼠，虽然它似乎并没有在大鼠暴露于急性应激功能活跃。因此，pPVTh似乎控制HPA活动的背景下，特别是以前的压力经验。在这个建议中，我们试图表征的神经回路介导的主要抑制作用的pPVTh HPA活动。pPVTh的传出投射是有限的，主要是边缘系统结构，包括杏仁核，前额皮质和床核的纹终纹，但也到下丘脑区域，可以更直接地控制HPA的活动。我们的一般假设是，pPVTh发挥其影响力，通过改变活动的边缘结构，但不是下丘脑结构，因为边缘区域更能够评估感官信息的背景下，过去的压力历史。更具体地说，我们将确定pPVTh是否可以通过作用于边缘GABA能系统（Aim 1）和/或通过充当慢性应激暴露释放的糖皮质激素的负反馈效应的位点（Aim 2）来对HPA活性发挥其抑制作用。目标3的重点是通过pPVTh内释放的胆囊收缩素改变HPA活性，特别是在慢性应激大鼠和目标4将研究中央CRF系统如何与pPVTh及其相关的边缘系统的相互作用的途径。鉴于pPVTh效应对慢性应激状态的特异性，表征这种pPVTh-边缘系统回路对于理解慢性应激与可能导致疾病的生理和行为变化之间的关联至关重要。

DESCRIPTION (provided by applicant): Chronic exposure to stress in the form of major adverse life events is associated with the development of disorders such as depression, anxiety and post-traumatic stress disorder and chronic fatigue syndrome. Changes in activity within the hypothalamic-pituitary-adrenal (HPA) axis are important features of these disorders and likely reflect plasticity in brain circuitry that coordinates these neuroendocrine responses with behavioral and autonomic function. Animals undergoing chronic stress exhibit many of the neuroendocrine autonomic and behavioral changes seen in individuals with disease. Using HPA activity as our primary endpoint, we have identified the posterior division of the paraventricular nucleus of the thalamus (pPVTh) as a critical mediator of HPA responses in chronically stressed rats though it does not seem to be functionally active in rats exposed to acute stress. Therefore, the pPVTh seems to control HPA activity specifically within the context of prior stress experience. In this proposal, we seek to characterize the neural circuits that mediate the primarily inhibitory effects of the pPVTh on HPA activity. The efferent projections of the pPVTh are limited and are primarily to limbic structures including the amygdala, prefrontal cortex and bed nucleus of the stria terminalis but also to a hypothalamic region that can more directly control HPA activity. Our general hypothesis is that the pPVTh exerts its influence through changing activity in limbic structures but not hypothalamic structures since limbic regions are more capable of evaluating sensory information within the context of past stress history. More specifically, we will determine whether the pPVTh can exert its inhibitory influence on HPA activity by acting on limbic GABA-ergic systems (Aim 1) and/or by serving as a site of negative feedback effects of glucocorticoids released by the chronic stress exposure (Aim 2). Aim 3 focuses on the pathways through which cholecystokinin released within the pPVTh alters HPA activity specifically in chronically stressed rats and Aim 4 will examine how central CRF systems interact with the pPVTh and its associated limbic circuitry. Given the specificity of pPVTh effects to the chronic stress state, characterizing this pPVTh-limbic circuitry is fundamental to understanding the association between chronic stress and changes in physiology and behavior that can lead to disease.