Social Regulation of Circadian Output Systems

昼夜节律输出系统的社会调节

• 批准号: 6766549
• 负责人: PHILIP K STODDARD
• 金额: $ 20.93万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6766549
• 关键词: adrenocorticotropic hormone; alternatives to animals in research; behavior test; behavioral /social science research tag; circadian rhythms; electrophysiology; environmental stressor; enzyme linked immunosorbent assay; ethology; fish; fish electric organ; genetically modified animals; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; male; neurochemistry; physiologic stressor; serotonin; socioenvironment

Circadian rhythms are often disrupted with advancing age and under conditions of stress, including social stress. Breakdown in human circadian rhythms are believed to occur most often downstream of the central circadian oscillator. Our lab has developed electric fish as a powerful non-mammalian vertebrate model system in which controlled changes in the social environment alter predictably the magnitude of two circadian rhythms in electric signal waveform parameters. Our system makes a valuable model because we have identified multiple social conditions that modulate circadian rhythm expression in multiple ways. As with mammalian models, situations promising social upheaval disrupt the circadian outputs. Social isolation, however, causes a progressive diminution of these rhythms, as though the coupling between the central oscillator and the peripheral effector had been weakened or broken. Restoration of favorable social conditions restores the strength of the rhythms. We have made significant progress in identifying the neurochemical components of the circadian output pathway. Two neurochemical messengers, 5-HT and ACTH, modulate the behavioral outputs, ACTH at the level of the peripheral effector organ. Results with males indicate that the circadian rhythms are regulated somewhere downstream of serotonin. We also have found that non-aromatizable androgens can enhance the amplitude of these circadian rhythms in a manner resembling certain favorable social manipulations. Building on our progress to date, we propose specific aims (1) to better understand the behavioral conditions that regulate circadian rhythms in the electric waveform, (2) to elucidate the roles of androgens and glucocorticoids in regulating the circadian rhythms, and (3) to identify which hormones of the hypothalamus-pituitary-adrenal axis are in direct control of the circadian outputs. Because the neuroanatomy and neurochemistry of the circadian control pathway have been conserved across vertebrate evolution, these studies will lead directly to testable hypotheses about mechanisms !underlying circadian rhythm pathologies in mammals, including humans.

昼夜节律通常会随着年龄的增长而被打乱，在压力条件下，包括社会压力。人类昼夜节律的崩溃被认为最常发生在中央昼夜节律振荡器下游。我们的实验室开发了电鱼作为一种强大的非哺乳动物脊椎动物模型系统，在该系统中，社会环境的可控变化可以预测地改变电信号波形参数中的两个昼夜节律的大小。我们的系统是一个有价值的模型，因为我们已经确定了以多种方式调节昼夜节律表达的多种社会条件。与哺乳动物模型一样，预示着社会动荡的情况会扰乱昼夜节律输出。然而，社会孤立导致了这些节奏的逐渐减弱，就好像中央和中央之间的耦合 振荡器和外围效应器已被削弱或损坏。恢复有利的社会条件会恢复节奏的力量。我们在鉴定昼夜节律输出通路的神经化学成分方面取得了重大进展。两种神经化学信使，5-羟色胺和ACTH，在外周效应器官水平上调节行为输出，ACTH。对男性的研究结果表明，昼夜节律受到5-羟色胺下游某处的调节。我们还发现，非芳香化雄激素可以增强这些昼夜节律的幅度，其方式类似于某些有利的社会操纵。根据我们迄今的进展，我们提出了具体的目标：(1)更好地了解在电波形中调节昼夜节律的行为条件，(2)阐明雄激素和糖皮质激素在调节昼夜节律中的作用，以及(3)确定下丘脑-垂体-肾上腺轴的哪些激素直接控制昼夜节律的输出。由于昼夜节律控制途径的神经解剖学和神经化学在脊椎动物进化过程中是保守的，这些研究将直接导致关于哺乳动物(包括人类)昼夜节律病理机制的可测试假说。