A role for the adrenal in the synchronization of circadian rhythms in the mouse

Circadian clocks (from the Lat. circa diem - about one day) allow the organism to anticipate time-of-day dependent environmental conditions, thus permitting an optimal adaptation to the habitat. Disruption of the circadian system - either genetic or by external perturbation such as jetlag - promotes the development of diseases such as diabetes, immune deficiency or cancer. At the molecular level circadian clocks are based on cell autonomous transcriptional feedback loops of clock genes/proteins. In mammals circadian timing is organized in a hierarchical system with a central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN) that receives external light information from the retina and resets peripheral clocks in other brain regions and throughout the body in a process called entrainment. While the molecular basics and physiological outputs of circadian timekeeping at the cellular and tissue levels have been extensively studied, remarkably little is known about the communication between different clocks of the body. While no general clock resetting signal has been identified, but both humoral and neuronal signals seem to be involved. Studies from our group and others suggest that the adrenal and the rhythmically secreted, adrenocortical clock regulated glucocorticoids may play an important role in this context.In this project we will use different transgenic mouse models to study the entrainment of the adrenal clock, its function in the synchronization of other circadian oscillators of the body as well as its role in the regulation of behavioral rhythms. Our findings will help to develop new therapeutic approaches for the treatment of disorders resulting from the disruption of circadian timing, e.g. during jetlag or shift work.

Die Regulation der Glukokortikoid-Stresshormone unterliegt einem ausgeprägten zirkadianen Rhythmus. Dieser wird durch innere, sog. zirkadiane Uhren reguliert. In diesem Projekt haben wir das Zusammenspiel zwischen zirkadianem und Stresssystem mit Fokus auf Rhythmen in der Nebenniere untersucht. Dazu haben wir eine Mauslinie mit spezifischer Deletion der Uhrenfunktion im adrenergen Kortex entwickelt und diese und andere uhrengendefiziente Tiere auf zirkadiane und Stressfunktionen hin untersucht. Insgesamt konnte das Zusammenspiel zwischen zirkadianem und Stresssystem weiter charakterisiert werden. Uhrendefiziente Tiere zeigen eine erhöhte Stressresistenz und verminderte Sekretion von Glukokortikoiden. Diese Stressresistenz scheint Nebennieren-vermittelt; allerdings ist die Uhrenfunktion in der Nebennierenrinde offenbar für diese Funktionen nicht essentiell. Weitere Experimente sind notwendig, um das Zusammenspiel zwischen verschiedenen zellulären Uhren in der Regulation der Glukokortikoid-Sekretion und deren Zielprozesse weiter zu analysieren.