Figure 5. The light-activated central CLOCK located in the SCN is orchestrating the daily rhythmic release of glucocorticoids by influencing the activity of the HPA axis through efferent connections from the SCN to the CRH/AVP-containing neurons of the PVN. Additionally, splanchnic nerve innervation to the adrenal medulla via SCN-ANS axis also contributes to circadian GC secretion and resets the adrenal local clock through modulating adrenal sensitivity to ACTH by the action of epinephrine. Secreted glucocorticoids in turn reset and phase-delay circadian rhythm of the peripheral CLOCKs by stimulating the expression of several CLOCK-related genes; this is especially important for temporal adjustment of body ’ s activity against stress. The peripheral CLOCKs also regulate glucocorticoid effect in local tissues through interaction between Clock/Bmal1 and GR, providing a local counter regulatory feedback loop to the effect of central CLOCK on the HPA axis. (Adapted from Nader, N, Chrousos, GP, Kino T. Trends Endocrinol Metab 2010;21:277).