Neural Circuitry Underlying Chronic Stress Effects

描述(申请人提供)：长期暴露在压力下的主要不良生活事件的形式与疾病的发展有关，如抑郁、焦虑、创伤后应激障碍和慢性疲劳综合症。下丘脑-垂体-肾上腺(HPA)轴内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功能。承受慢性应激的动物表现出许多与疾病患者相同的神经内分泌、自主神经和行为变化。以HPA活性为主要终点，我们发现丘脑室旁核后分(PPVTh)是慢性应激大鼠HPA反应的关键介质，尽管它在急性应激大鼠中似乎并不活跃。因此，pPVTh似乎在先前应激经验的背景下特定地控制HPA的活动。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，主要投射到边缘结构，包括杏仁核、前额叶皮质和终纹床核，但也投射到更直接控制HPA活动的下丘脑区域。我们的一般假设是，pPVTh通过改变边缘结构而不是下丘脑结构的活动来发挥其影响，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是否通过作用于边缘GABA能系统(目标1)和/或作为慢性应激释放的糖皮质激素负反馈效应的部位(目标2)对HPA活性产生抑制影响。目标3重点研究在pPVTh内释放的CCK改变HPA活性的途径，目标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效应对慢性应激状态的特异性，确定这种pPVTh-边缘回路的特征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是基本的。

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.