Glucocorticoid Negative Feedback: Intrinsic and Extrinsic Mechanisms

糖皮质激素负反馈：内在和外在机制

基本信息

批准号：
8294570
负责人：
ROBERT L SPENCER
金额：
$ 37.62万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-20 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8294570
关键词：
Acute Address Adverse effects Anxiety Anxiety Disorders Behavior Biological Bipolar Disorder Brain Brain region CRH gene Cells Characteristics Chronic Chronic Fatigue Syndrome Chronic stress Circadian Rhythms Corticosterone Development Disease Elements Emotional Emotions Etiology Feedback Gene Expression Genes Glucocorticoids Glutamates Health Hormones Human Hypothalamic structure Impairment Individual Intervention Knowledge Lead Learning Location MAP Kinase Gene Measures Medial Mediating Mediator of activation protein Mental Depression Mental Health Mental disorders Molecular Neuraxis Neuronal Plasticity Neurons Neurophysiology - biologic function Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Organ Pathway interactions Pattern Peripheral Phase Physiological Play Post-Traumatic Stress Disorders Prefrontal Cortex Psychological Stress Publishing Rattus Regulation Relative (related person)Reporting Research Research Project Grants Risk Risk Factors Role Signal Transduction Site Stress System Time Tissues Work acute stress base design experience gene function hypothalamic-pituitary-adrenal axis in vivo neural circuit neuroregulation paraventricular nucleus patient population physical conditioning prevent receptor research study response restraint stress related disorder suprachiasmatic nucleus therapy design time interval

项目摘要

DESCRIPTION (provided by applicant): Glucocorticoid hormones have powerful multifactorial regulatory effects on every physiological system. Dysregulated patterns of glucocorticoid hormone secretion, often as a result of chronic stress, have adverse effects on physical and mental health. Dysregulation of glucocorticoid secretion is strongly associated with some psychological disorders (e.g. depression and posttraumatic stress disorder) and other biomedical disorders (e.g. Type II diabetes, chronic fatigue syndrome, fibromyalgia). Glucocorticoid secretion is controlled by the neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis system, and the principal factor that has regulatory control over HPA axis activity is glucocorticoid negative feedback. Understanding of the mechanisms responsible for glucocorticoid negative feedback is limited. To address that gap in knowledge, this ongoing research project will determine the molecular, cellular and systems level mechanisms of glucocorticoid negative feedback. This knowledge is necessary to discern how chronic stress leads to altered glucocorticoid negative feedback function, and it will point to new strategies for targeted interventions that will prevent and perhaps reverse alteration of glucocorticoid negative feedback function associated with chronic stress. The guiding hypothesis of this project is that glucocorticoids produce multiple effects within the intrinsic anatomical elements of the HPA axis as well as effects on neural circuits that dictate the moment-to-moment HPA axis activity. These glucocorticoid effects have distinct time frames of onset and expression, as well as separate underlying molecular mechanisms. By establishing these cellular sites of action and temporal patterns of expression this project will determine specific mechanisms of glucocorticoid negative feedback. Previous work on this project identified independent actions of glucocorticoids that are evident within different time intervals after a phasic increase in glucocorticoids that can be distinguished as fast (< 15 min), short-term (~ 1 hr), and delayed (~3 hr) negative feedback actions. Four Specific Aims organized around this conceptual framework will address the following: Aim 1] To determine the temporal requirements and receptor mechanisms by which glucocorticoids produce fast negative feedback at the hypothalamic paraventricular nucleus. Aim 2] To use hypothalamic organotypic cultures to determine cellular and molecular mechanisms by which glucocorticoids produce intrinsic negative feedback on CRH neurons. Aim 3] To determine in vivo mechanisms of glucocorticoid short-term and delayed negative feedback. Aim 4] To determine the relationship between chronic stress adaptation and glucocorticoid negative feedback function. The new information derived from these proposed studies can then be applied to 1) the design of better (more sensitive or revealing) HPA axis related measures and challenge conditions in patient populations, 2) identification of new candidate risk genes associated with HPA axis dysregulation, and 3) development of new treatments that may selectively normalize HPA axis function without disturbing appropriate glucocorticoid signaling throughout the body.

描述（由申请人提供）：糖皮质激素对每个生理系统都具有强大的多因素调节作用。糖皮质激素分泌失调通常是由于慢性压力造成的，对身心健康产生不利影响。糖皮质激素分泌失调与一些心理疾病（例如抑郁症和创伤后应激障碍）和其他生物医学疾病（例如II型糖尿病、慢性疲劳综合征、纤维肌痛）密切相关。糖皮质激素的分泌受神经内分泌下丘脑-垂体-肾上腺（HPA）轴系统控制，对HPA轴活动具有调节控制作用的主要因素是糖皮质激素负反馈。对糖皮质激素负反馈机制的了解有限。为了解决这一知识差距，这个正在进行的研究项目将确定糖皮质激素负反馈的分子、细胞和系统水平机制。这些知识对于辨别慢性压力如何导致糖皮质激素负反馈功能改变是必要的，并且它将指出有针对性的干预措施的新策略，以防止甚至可能逆转与慢性压力相关的糖皮质激素负反馈功能的改变。该项目的指导性假设是糖皮质激素在 HPA 轴的内在解剖元素内产生多种作用，并对决定即时 HPA 轴活动的神经回路产生影响。这些糖皮质激素作用具有不同的起效和表达时间框架，以及单独的潜在分子机制。通过建立这些细胞作用位点和表达的时间模式，该项目将确定糖皮质激素负反馈的具体机制。该项目之前的工作确定了糖皮质激素的独立作用，这些作用在糖皮质激素阶段性增加后的不同时间间隔内很明显，可以区分为快速（< 15 分钟）、短期（约 1 小时）和延迟（约 3 小时））负反馈行为。围绕这一概念框架组织的四个具体目标将解决以下问题：目标 1] 确定糖皮质激素在下丘脑室旁核产生快速负反馈的时间要求和受体机制。目标 2] 使用下丘脑器官型培养物确定糖皮质激素对 CRH 神经元产生内在负反馈的细胞和分子机制。目标 3] 确定糖皮质激素短期和延迟负反馈的体内机制。目的4]确定慢性应激适应与糖皮质激素负反馈功能之间的关系。从这些拟议研究中获得的新信息可以应用于 1) 设计更好的（更敏感或更具揭示性的）HPA 轴相关措施和患者群体的挑战条件，2) 识别与 HPA 轴失调相关的新候选风险基因， 3) 开发新的治疗方法，可以选择性地使 HPA 轴功能正常化，而不干扰全身适当的糖皮质激素信号传导。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inescapable but not escapable stress leads to increased struggling behavior and basolateral amygdala c-fos gene expression in response to subsequent novel stress challenge.

DOI：
10.1016/j.neuroscience.2010.06.052
发表时间：
2010-09-29
期刊：
NEUROSCIENCE
影响因子：
3.3
作者：
Weinberg, M. S.;Grissom, N.;Paul, E.;Bhatnagar, S.;Maier, S. F.;Spencer, R. L.
通讯作者：
Spencer, R. L.

Adrenal-dependent diurnal modulation of conditioned fear extinction learning.

DOI：
10.1016/j.bbr.2015.03.006
发表时间：
2015-06-01
期刊：
BEHAVIOURAL BRAIN RESEARCH
影响因子：
2.7
作者：
Woodruff, Elizabeth R.;Greenwood, Benjamin N.;Chun, Lauren E.;Fardi, Sara;Hinds, Laura R.;Spencer, Robert L.
通讯作者：
Spencer, Robert L.

Medial prefrontal cortex activity can disrupt the expression of stress response habituation.