Perinatal Programming of Circadian Clock-Stress Crosstalk

Figure 1

Clock-stress coupling at systemic and molecular levels. (a) The circadian clock and stress systems influence each other’s activity at multiple and reciprocal levels. The central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is under the regulation of the light input from the retina. SCN controls the circadian function of the hypothalamus-pituitary-adrenal (HPA) axis to induce a rhythmic production and secretion of glucocorticoid (GCs) hormones from the adrenal glands. Via autonomic nervous system (ANS) pathways, the SCN further synchronizes adrenal clocks to regulate the sensitivity of the steroidogenic machinery to adrenocorticotropic hormone (ACTH) stimulation. Peripheral clocks in liver, adipose tissue, and kidney are regulated by the SCN through the ANS and rhythmic entraining signals such as GCs. During acute stress, brainstem and limbic forebrain nuclei activate the HPA axis through the paraventricular nucleus (PVN) of the hypothalamus, resulting in the acute production of GCs by the adrenal cortex. About one hour after acute stress stimulation, GC levels return to baseline due to the activation of a negative feedback mechanism. GCs inhibit the synthesis of corticotropin-releasing hormone (CRH) in the PVN and ACTH in the pituitary, downregulating the stress system activity and shutting down steroid production at the level of the adrenal cortex. (b) The coupling between the circadian clock and the stress system relays, at molecular level, on two parallel transcriptional-translational feedback loops (TTLs) that modulate each other. Hormone-bound GR binds glucocorticoid responsive elements (GREs) in the promoter region of several clock genes and various clock-controlled genes. Conversely, CLOCK (CL)/BMAL1 (BM) heterodimers (active during the night) interact physically and acetylate GR, thereby reducing its affinity to GREs and its translocation into the nucleus. CRY1 and CRY2 can interact with the C-terminal domain of GR in a ligand-dependent fashion, repressing the GR-mediated transactivation of certain target genes. Additionally, REV-ERBα (active during the day as an inhibitor of BMAL1 expression) can stabilize the nuclear localization of GR reinforcing its transcriptional activity, through its interaction with heat shock protein 90 (HSP90). Several genes contain both, GRE and E-box elements in the promoters being regulated by both loops. Through this complex network of interactions, GR and the clock machinery finally translate environmental information in physiological responses.

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