The suprachiasmatic nucleus gets split: why does cortisol respond but not ACTH?

In mammals, circadian timing is dependent on a pacemaker or clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus (1). The clock is reset daily by environmental lighting transmitted to the SCN from the retina via the retinohypothalamic pathway (2). This mechanism guarantees that daily rhythms in behavior and physiology including hypothalamic-pituitary-adrenal (HPA) activity are coordinated with the daily light-dark cycle. The HPA axis is characterized by a prominent circadian rhythm that is essential for providing circulating glucocorticoids to support metabolic, cardiovascular, and neuronal processes at the onset of daily activity periods. Circadian rhythms in adrenal corticosterone are driven by in-phase rhythms in plasma ACTH and in adrenal sensitivity to ACTH (3). Adrenal sensitivity is modulated by splanchnic neural activity (4, 5). Taken together, these findings have led to the hypothesis that rhythms in adrenal secretion of glucocorticoids are regulated by not only pituitary ACTH but also sympathetic adrenal innervation (6, 7). In the present issue of Endocrinology, Lilley et al. (8) provide novel results supporting the existence of pathways from the SCN that could subserve dual regulation of glucocorticoid rhythmicity. In this study, Syrian golden hamsters were induced to split rhythms of locomotor activity by exposure to constant light. As shown previously, the split rhythm is manifested as two bouts of locomotor activity separated by approximately 12 h (9, 10). The episodes of locomotion are thought to result from the activity of two coupled circadian oscillators cycling in antiphase ( 12 h out of phase) corresponding to the left and right SCN nuclei (10). By collecting serial blood samples at 1-h intervals throughout a 24-h period in awake hamsters, the study by Lilley et al. (8) showed a clear difference in cortisol rhythms between split and unsplit animals. Whereas unsplit control hamsters showed a single peak of cortisol that preceded a single period of locomotor activity, the split hamsters showed two peaks of cortisol separated by approximately 12 h that were associated temporally with the split rhythm in locomotion. This unique observation is consistent with the hypothesis that dual SCN oscillators are capable of controlling glucocorticoid secretion. Nonetheless, these data do not answer the major question: are there pathways from the SCN that sustain glucocorticoid rhythmicity by activating both HPA and sympathoadrenal systems? To address this issue, the investigators completed another experiment to examine whether peaks in plasma cortisol are associated temporally with peaks in ACTH. To overcome the technical hurdle of obtaining a sufficient sample volume to measure ACTH without activating a hypovolemia-induced stress response, samples were collected at 3-h intervals, a sampling frequency still sufficient to characterize rhythmicity. Results showed that in unsplit control hamsters, a single peak in plasma ACTH was associated with the peak in plasma cortisol. The unexpected finding, however, was that split hamsters showing two peaks in cortisol showed no peaks in plasma ACTH. This finding supports the hypothesis that an extra-ACTH mechanism is responsible for regulating cortisol secretion in the split hamster. The investigators propose that sympathoadrenal control of glucocorticoid secretion is the extra-ACTH mechanism [Fig. 3 (8)]. Although experimental results are not presented, there is compelling evidence to support this conjecture. The adrenal cortex receives sympathetic in-