Glucocorticoid Negative Feedback: Intrinsic and Extrinsic Mechanisms

糖皮质激素负反馈：内在和外在机制

• 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
• 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

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具有强大的多因子调节作用。糖皮质激素分泌失调通常是长期压力造成的，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障碍（如抑郁症和创伤后应激障碍）和其他生物医学障碍（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系统下丘脑-垂体-肾上腺（HPA）轴系统的控制，而对HPA轴活动起调节作用的主要因素是糖皮质激素的负反馈。对糖皮质激素负反馈机制的理解是有限的。为了解决这一知识空白，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应激如何导致糖皮质激素负反馈功能改变是必要的，并且它将指向针对性干预的新策略，这些干预将防止并可能逆转与慢性应激相关的糖皮质激素负反馈功能的改变。该项目的指导假设是，糖皮质激素在HPA轴的内在解剖学元素内产生多种效应，以及对决定HPA轴活动的神经回路的影响。这些糖皮质激素效应具有不同的发作和表达时间范围，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。该项目的先前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是明显的，可以区分为快速（< 15分钟），短期（约1小时）和延迟（约3小时）负反馈作用。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。目的2]利用下丘脑器官型培养物研究糖皮质激素对CRH神经元产生内在负反馈的细胞和分子机制。[目的3]探讨糖皮质激素短期和延迟负反馈的体内机制。目的4]探讨慢性应激适应与糖皮质激素负反馈功能的关系。从这些拟议的研究中获得的新信息可以应用于1）设计更好的（更敏感或更有启发性的）HPA轴相关测量和患者群体中的激发条件，2）鉴定与HPA轴失调相关的新的候选风险基因，和3）开发可以选择性地使HPA轴功能正常化而不干扰整个身体的适当糖皮质激素信号传导的新治疗。

项目成果

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.

Diurnal Corticosterone Presence and Phase Modulate Clock Gene Expression in the Male Rat Prefrontal Cortex.

• DOI: 10.1210/en.2015-1884
• 发表时间: 2016-02
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: E. Woodruff;L. Chun;Laura R. Hinds;R. Spencer

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

• DOI: 10.1016/j.neuroscience.2010.04.006
• 发表时间: 2010-07-14
• 期刊: NEUROSCIENCE
• 影响因子: 3.3
• 作者: Weinberg, M. S.;Johnson, D. C.;Bhatt, A. P.;Spencer, R. L.
• 通讯作者: Spencer, R. L.

Influence of Pre-Training Predator Stress on the Expression of c-fos mRNA in the Hippocampus, Amygdala, and Striatum Following Long-Term Spatial Memory Retrieval.

• DOI: 10.3389/fnbeh.2011.00030
• 发表时间: 2011
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3
• 作者: Vanelzakker MB;Zoladz PR;Thompson VM;Park CR;Halonen JD;Spencer RL;Diamond DM
• 通讯作者: Diamond DM