Circadian clocks of the adrenal medulla

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A network of cellular circadian clocks regulates 24-h rhythms of physiology and behavior, adapting the organism to recurring changes in the external environment brought about by the Earth's rotation around its axis. At the molecular level, a set of clock genes organized in a system of interlocked transcription-translational feedback loops drive rhythmic activation of tissue-specific transcriptional programs to coordinate cellular physiology along the 24-h day. Activity of the hypothalamus-pituitary-adrenal (HPA) stress axis is under strict circadian control with peak activity at the beginning of the active period, i.e. the morning in man and the evening in nocturnal rodents. We have previously shown that circadian clocks regulate secretion of glucocorticoids (GCs) from the adrenal under baseline conditions in response to stress. Transplantation experiments in mice further suggested that adrenal clocks gate the sensitivity of GC responses to incoming stimuli. Genetic experiments further suggested that adrenocortical clock function is dispensable for circadian and stress-induced GC release, pointing at a role of the adrenomedullary clock in this context. To test this, we will in this project generate mice with specific disruption of clock function in the adrenal medulla and characterize circadian and stress-related HPA axis activity and tissue clock regulation in these animals. We will further dissect the communication pathways between adrenal medulla and GC-producing cortical cells underlying the circadian gating of the steroidogenic machinery using both in-vivo and ex-vivo approaches.