Neural Circuitry Underlying Chronic Stress Effects

描述（由申请人提供）：长期暴露于主要不良生活事件形式的压力与抑郁症、焦虑、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，可能反映了协调这些神经内分泌反应与行为和自主神经功能的脑回路的可塑性。经历慢性应激的动物表现出许多与疾病个体相同的神经内分泌、自主神经和行为改变。以HPA活性为主要终点，我们确定了丘脑室旁核后段（pPVTh）是慢性应激大鼠HPA反应的关键介质，尽管它在暴露于急性应激的大鼠中似乎没有功能活性。因此，pPVTh似乎在先前压力经历的背景下特异性地控制HPA活动。在这项提议中，我们试图描述介导pPVTh对HPA活性的主要抑制作用的神经回路。pPVTh的传出投射是有限的，主要投射到包括杏仁核、前额叶皮层和终纹床核在内的边缘结构，但也投射到下丘脑区域，该区域可以更直接地控制HPA活动。我们的一般假设是，pPVTh通过改变边缘结构的活动而不是下丘脑结构的活动来施加其影响，因为边缘区域更有能力评估过去应激史背景下的感觉信息。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（目的1）和/或作为慢性应激暴露释放的糖皮质激素负反馈效应的一个位点（目的2）来发挥其对HPA活性的抑制作用。Aim 3关注慢性应激大鼠pPVTh内释放的胆囊收缩素改变HPA活性的途径，Aim 4将研究中枢CRF系统如何与pPVTh及其相关的边缘回路相互作用。鉴于pPVTh对慢性应激状态的特异性影响，表征pPVTh-边缘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系至关重要。

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.