CORTISOL FEEDBACK IN DIURNAL RHYTHM OF HPA AXIS

HPA 轴昼夜节律中的皮质醇反馈

• 批准号: 3475232
• 负责人: ELIZABETH ANN YOUNG
• 金额: $ 9.38万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3475232
• 关键词: biological information processing; circadian rhythms; corticosteroid receptors; cortisol; hippocampus; hormone regulation /control mechanism; hypothalamus; laboratory rat; neuroendocrine system; pituitary adrenal axis; pituitary gland; proopiomelanocortin; radioimmunoassay; skeletal stress; tissue /cell culture

Glucocorticoids are secreted in times of stress to provide a host of physiological responses necessary to cope with the stress. However, an excess of glucocorticoids are harmful to the organism. Thus, it is necessary to regulate secretion of glucocorticoids to prevent over-secretion. This is accomplished through negative feedback at a number of sites. The turning off of secretion during the rising phase of corticosteroid secretion following stress is known as fast feedback. In addition, there is a level sensitive feedback that is proportional to the amount of glucocorticoid secreted with the stressor. This proportional feedback occurs several hours following the stress and is easily demonstrated in vitro at the pituitary. Besides stress induced rises in glucocorticoid there is a strong circadian rhythm that drives glucocorticoids to stress induced levels at the zenith while clamping glucocorticoids to very low levels at the nadir. Negative feedback is clearly involved in regulating this rhythm. This circadian rhythm provides a naturalistic model for understanding these various feedback types. This project examines the interface of neuronal circuits with glucocorticoid feedback and its impact on circadian rhythm. Specifically, two hypotheses are tested: 1) that there is a critical low point of cortisol necessary to resensitize the receptor and trigger the circadian drive; or 2) that absolute levels are less critical than a variation between the high and low points of the rhythm, i.e., a flattened rhythm produces abnormalities of cortisol feedback. To test these hypotheses, three different corticosterone preparations of varying lengths of action administered in the zenith vs. the nadir of the time rhythm will be measured administered. Glucocorticoid feedback will be measured with two paradigms -- in vitro in short-term anterior pituitary suspensions and in vivo using a stress-fast feedback model. This fast feedback model tests the ability of neuronal circuits to terminate stress induced CRH release. The changes in these feedback measures will be correlated with direct measurement of glucocorticoid receptors in the hippocampus, hypothalamus and anterior pituitary. Such studies will help in sorting out if there are feedback changes that are not dependent upon changes in glucocorticoid receptors, and provide paradigms for studying the mechanisms underlying these forms of feedback. These studies will provide further leads for studying the connection between the brains's role in HPA axis changes in depression.

糖皮质激素在压力时期分泌，以提供大量的 应对压力所必需的生理反应。然而，一个 糖皮质激素过量对机体有害。因此，它是 有必要调节糖皮质激素的分泌，以防止 过度分泌。这是通过大量的负面反馈来实现的 网站的数量。在上升阶段关闭分泌物。 应激后皮质类固醇的分泌被称为快速反馈。在……里面 此外，还有一个水平敏感的反馈与 应激源分泌的糖皮质激素的量。这个比例 压力过后几个小时就会出现反馈，而且很容易 在脑下垂体部进行了体外实验。除了压力导致的上升外， 糖皮质激素有强烈的昼夜节律 夹闭时天顶应激诱导的糖皮质激素水平 糖皮质激素水平在最低点非常低。负面反馈是 显然参与了对这种节奏的调节。这种昼夜节律提供了 理解这些不同反馈类型的自然主义模型。这 该项目研究了神经元回路与糖皮质激素的接口 反馈及其对昼夜节律的影响。具体地说，有两个假设 测试结果：1)皮质醇存在一个临界低点 使受体重新敏感并触发昼夜节律驱动；或2) 绝对水平没有高水平和低水平之间的变化重要 节奏点，即平坦的节奏会产生异常的 皮质醇反馈。为了验证这些假说，三种不同的皮质酮 在天顶给药的不同时间长短的制剂与。 时间节律的最低点将被测量和实施。糖皮质激素 反馈将用两种范式来衡量--短期内的体外反馈 应用应激快速反馈的垂体腺前叶悬吊和活体实验 模特。这个快速反馈模型测试了神经元回路的能力 终止应激诱导的CRH释放。这些反馈中的变化 测量将与糖皮质激素的直接测量相关 海马体、下丘脑和垂体前叶的受体。是这样的 研究将有助于理清是否有未发生的反馈变化 依赖于糖皮质激素受体的变化，并提供范例 来研究这些形式的反馈背后的机制。这些 研究将为研究两者之间的联系提供进一步的线索 在抑郁症中，大脑在HPA轴变化中的作用。