Social Regulation of Circadian Output Systems

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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.