Neural Circuitry Underlying Chronic Stress Effects

慢性压力影响下的神经回路

• 批准号: 6844918
• 负责人: SEEMA BHATNAGAR
• 金额: $ 17.49万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844918
• 关键词: behavioral habituation /sensitization; brain electrical activity; cholecystokinin; chronic disease /disorder; corticotropin releasing factor; gamma aminobutyrate; glucocorticoids; hypothalamic pituitary adrenal axis; laboratory rat; limbic system; neuroanatomy; paraventricular nucleus; psychological stressor

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.

描述（由申请人提供）：重大不良生活事件形式的长期暴露于压力与抑郁症，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）轴的活性变化是这些疾病的重要特征，并且可能反映了脑电路中的可塑性，可将这些神经内分泌反应与行为和自主功能保持协调。患有慢性压力的动物表现出许多在疾病个体中看到的许多神经内分泌自主神经和行为变化。以HPA活性为主要终点，我们已经确定了丘脑（PPVTH）的室室核的后部分裂是长期压力大鼠中HPA反应的关键介质，尽管它似乎在暴露于急性应激的大鼠中有功能活性。因此，PPVTH似乎在先前的压力经验的背景下专门控制HPA活动。在此提案中，我们试图表征介导PPVTH对HPA活性的主要抑制作用的神经回路。 PPVTH的传出投影受到限制，主要用于边缘结构，包括杏仁核，前额叶皮层和层末端的床核，以及可以更直接控制HPA活性的下丘脑区域。我们的一般假设是，PPVTH通过边缘结构的活动变化而不是下丘脑结构产生影响，因为边缘区域更有能力在过去的压力史上评估感觉信息。更具体地说，我们将确定PPVTH是否可以通过作用于边缘GABA-CREGIC系统（AIM 1）和/或作为慢性应激暴露释放糖皮质激素的负面反馈效应的部位来确定其对HPA活性的抑制作用（AIM 2）。 AIM 3的重点是在PPVTH中释放的胆囊化蛋白在慢性压力大鼠中释放的HPA活性，AIM 4将检查中央CRF系统如何与PPVTH及其相关的缘缘电路相互作用。鉴于PPVTH效应对慢性应激状态的特异性，表征这种PPVTH-LIMBIC回路对于理解慢性应激与生理和行为变化之间的关联至关重要，这可能导致疾病。