Social Regulation of Circadian Output Systems

随着年龄的增长和压力条件（包括社会压力），昼夜节律经常被打乱。人类昼夜节律的中断被认为最常发生在中央昼夜节律振荡器的下游。我们的实验室已经开发出电鱼作为一种强大的非哺乳动物脊椎动物模型系统，其中社会环境的受控变化可预测地改变电信号波形参数中两个昼夜节律的幅度。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，有可能发生社会动荡的情况会破坏昼夜节律输出。然而，社会隔离会导致这些节奏的逐渐减弱，就像中央和中央之间的耦合一样

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.