The regulation of circadian glucocorticoid (GC) secretion is one of the best-studied examples of circadian coordination involving a cooperation between the SCN, the autonomic system and adrenocortical clocks
[50][58]. The SCN, via the activation of corticoliberin (CRH) secretion from the paraventricular nucleus of the hypothalamus (PVN), controls the rhythmic release of adrenocorticotropic hormone (ACTH) from the pituitary. ACTH, in turn, stimulates GC production in
zona fasciculata cells of the adrenal cortex. Via another route involving autonomic pathways, either directly to the adrenal cortex or through connections with the adjacent medulla, the SCN synchronizes adrenal clocks, thereby regulating the sensitivity of the steroidogenic machinery to ACTH stimulation
[11][50][51][13,58,59]. Transplantation and knock-down studies suggest that this sensitivity is gated by the adrenal clock. The adrenal gland is more sensitive to ACTH just before the onset of the activity period—as a result, with the same ACTH stimulus the adrenal cortex releases more corticosterone at the beginning of the activity period than at the beginning of the sleep period
[50][52][58,60]. GC effects are primarily exerted by the glucocorticoid receptor (GR), which is widely expressed throughout the body and within the brain (reviewed by
[53][61]) with the noted exception of the SCN
[54][62]. GCs also bind to and activate the mineralocorticoid receptor (MR) whose expression is restricted to certain tissues
[55][63]. Due to the higher GC affinity to MR, this receptor is tonically activated while GRs are activated only during peaks of ultradian GC pulses or during acute stress responses
[56][64]. GRs act as ligand-activated transcription factors. Upon GC binding, GRs translocate from the cytosol to the nucleus, bind to GRE (glucocorticoid responsive element) DNA motifs in regulatory regions of target genes and modulate transcriptional activity. The daily peak of GCs is synchronized with the need to mobilize energy from tissue stores anticipating the active phase, e.g., promoting gluconeogenesis and glucose release from the liver
[57][65] and fatty acids release from adipose tissues
[58][66]. GR signalling and the molecular clock machinery interact in multiple and reciprocal ways. Hormone-bound GR binds GREs in the promoter regions of several clock genes
[59][67]. Moreover, several clock proteins regulate GR intracellular localization and activity. These multiple bi-directional interactions explain the role of GCs as a major entrainment signal and their role in gating the sensitivity of peripheral tissue to systemic signals across the day (reviewed by
[53][61]).
Melatonin is considered as another key-synchronizing signal, since it exhibits a strong circadian rhythmicity with higher levels during the night (in phase and in anti-phase with GC rhythms in nocturnal and diurnal animals, respectively). In most mammals, rhythmic release of melatonin is regulated by light through sympathetic neuronal connections from the SCN to the pineal gland
[1][3]. Melatonin signal is transduced by G protein-coupled receptors expressed in the SCN, the pituitary and several peripheral organs such as adrenal glands, lung, heart, liver, etc. (reviewed by
[60][68]). For instance, melatonin signalling has been involved in transmitting seasonal day length information to the pars tuberalis, and the circadian regulation of insulin secretion and blood glucose levels
[61][69].
Early studies showed that autonomic nerve activity changes after light exposure while this effect is absent in SCN-lesioned animals
[62][70]. Later, tracing techniques demonstrated that the SCN is connected with several peripheral organs such as adipose tissue, adrenal, heart, liver, ovary, kidney, pancreas, etc.
[63][64][65][66][67][68][69][71,72,73,74,75,76,77]. A combination of tracing techniques and selective denervation also revealed that the SCN is connected with these organs through sympathetic and parasympathetic pre-ganglionic neurons
[70][78]. For instance, leptin, a hormone secreted by adipose tissue, displays a diurnal pattern that is controlled by the SCN through the sympathetic innervation
[71][79]. Although leptin induces phase advances in SCN slices, it may not shift the activity rhythm in vivo but instead potentiate the phase-shifting effect of a light pulse in the late subjective night
[72][73][80,81]. Electrophysiological experiments demonstrate that the connections of the SCN with neuroendocrine centres in the hypothalamus are physically separated from autonomic connections representing an independent communication route to the periphery
[74][75][82,83].