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The Suprachiasmatic Nucleus Gets Split: Why Does
Cortisol Respond But Not ACTH?
William C. Engeland and J. Marina Yoder
Department of Neuroscience, Graduate Program in Neuroscience, University of Minnesota, Minneapolis,
Minnesota 55455
n 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
I
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-
ISSN Print 0013-7227 ISSN Online 1945-7170
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/en.2011-2082 Received December 6, 2011. Accepted December 8, 2011.
Abbreviations: HPA, Hypothalamic-pituitary-adrenal; PVN, paraventricular nucleus; SCN,
suprachiasmatic nucleus.
For article see page 732
546
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Endocrinology, February 2012, 153(2):546 –548
Endocrinology, February 2012, 153(2):546 –548
nervation either directly or via connections with the adjacent adrenal medulla (11), and stimulation of the
splanchnic nerve increases glucocorticoid secretion (12,
13). Use of the split hamster represents an excellent model
for assessing the functional relevance of sympathetic neural input to the adrenal on glucocorticoid rhythmicity.
Experiments that have been successful in rats including
assessing adrenal sensitivity to ACTH (5), and testing responses to adrenal denervation (4, 5, 14) would be instructive in examining whether adrenal sympathetic activity in hamsters is the requisite extra-ACTH mechanism.
It is likely that results from these or similar experiments
will be forthcoming.
As indicated by Lilley et al. (8), entrainment of glucocorticoid rhythms by the SCN requires synchronization of an
adrenal clock mechanism. Adrenal cells express rhythms in
circadian clock genes (15), and an adrenal clock has been
implicated in controlling glucocorticoid rhythmicity by gating adrenal sensitivity to ACTH (16). Split hamsters express
adrenal clock genes asymmetrically with left and right adrenals, like SCN nuclei, oscillating in antiphase (17); these
sided differences are consistent with regulation of the
phase of the adrenal clock by a neural pathway. In conjunction with the results by Lilley et al. (8), it is reasonable
to propose that lateralization of SCN activity is transmitted via sympathetic nerves to the adrenals, resulting in
desynchronized left and right adrenal clocks that drive the
split cortisol rhythm. However, it also is possible that sympathetic input is regulating cortisol rhythms independently of an adrenal clock mechanism.
The capability of the adrenal clock to support glucocorticoid rhythms in vivo has been assessed using the MC2RAS-BMAL transgenic mouse, an adrenal cortex-specific
clock gene knockdown (18). When wild-type rodents are
placed in constant dark, eliminating SCN-dependent light
entrainment, free-running adrenal corticosteroid rhythms
are observed that parallel rhythms in clock gene expression
(18, 19). In contrast, MC2R-AS-BMAL mice show no corticosteroid rhythm in constant dark, indicating that the adrenal cortical clock mediates the free-running corticosterone rhythm. However, when MC2R-AS-BMAL mice are
entrained to a light-dark cycle, corticosterone rhythms
persist despite the absence of an adrenal clock (18). These
results indicate that glucocorticoid rhythms are generated
in vivo both by adrenal clock-dependent and clock-independent mechanisms. Thus, it will be important to determine whether the extra-ACTH mechanism that controls
cortisol secretion in split hamsters acts via the adrenal
clock.
In addition to examining peripheral control mechanisms, the split hamster could be informative in more
clearly defining the hypothalamic circuits that underlie
endo.endojournals.org
547
dual control of glucocorticoid rhythms. A previous study
by de la Iglesia et al. (20) showed that lateralization of SCN
activity drives sided differences in neuroendocrine output.
Split female hamsters show two LH surges, one preceding
each bout of locomotion (9). To determine the hypothalamic basis for the pituitary response, GnRH neuronal
activation was monitored; hamsters showed parallel leftright asymmetry in Fos expression in the SCN and in preoptic area GnRH neurons, suggesting that each LH surge
was mediated by sided SCN-preoptic pathways. A similar
approach could be used to identify pathways from the
SCN to the paraventricular nucleus (PVN) that control the
split cortisol rhythm. It is of interest that split hamsters
express sided differences in vasopressin-expressing SCN
neurons (10) because these neurons have been implicated
in controlling glucocorticoid rhythms in rats. Release of
vasopressin by SCN neurons in the PVN is an important
element of the hypothalamic circuit controlling corticosteroid secretion (21, 22). However, it remains unclear
whether vasopressin or other SCN-derived neurotransmitters affect the HPA, the sympathoadrenal, or both systems (23). The PVN is comprised of different neuronal
subpopulations, some projecting to the median eminence
that release CRH to control ACTH and others projecting
to the intermediolateral nucleus of the spinal cord to control sympathetic activity (24). This neuronal topography
has been established for the hamster PVN (25, 26). In
addition, hamsters with split rhythms show sided differences in the activation of subpopulations of PVN neurons (27). It would be of much interest to determine
whether cortisol peaks are preceded by activation of
CRH neurons, preautonomic neurons, or both. Although these experiments would be challenging, they
would offer the opportunity to more clearly delineate
the hypothalamic pathways from the SCN that underlie
light-dark entrainment of glucocorticoid rhythms via
HPA and sympathoadrenal axes.
In observing that the split rhythm in cortisol occurs
without an ACTH peak, the study by Lilley et al. (8) also
addresses the important issue of why rhythmic ACTH is
absent. It turns out that the bimodal pattern of cortisol
release in split hamsters results in lower total daily cortisol.
In secreting less cortisol, one would predict that reduced
steroid negative feedback in split hamsters would result in
increased secretion of ACTH. Instead, the absence of the
ACTH peak is attributed to heightened negative feedback
produced by the timing of cortisol exposure, two peaks
separated by approximately 12 h compared with a single
daily peak. Certainly there is a precedent for differential
feedback sensitivity to corticosteroids across the day (28).
In rats, corticosteroids are more effective in inhibiting
ACTH at the nadir compared with the peak of the circa-
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Engeland and Yoder
Splitting the Cortisol Rhythm in Hamsters
dian rhythm. It is possible that exposure to glucocorticoids
at both phases of the rhythm would be more effective in
suppressing ACTH secretion. However, any experiments
to address this issue would need to take into account the
time domain in which steroids act to suppress the specific
steroid receptor involved and the duration of the feedback
effect (29).
Endocrinology, February 2012, 153(2):546 –548
13.
14.
15.
Acknowledgments
Address all correspondence and requests for reprints to: W. C.
Engeland, Ph.D., Department of Neuroscience, , University of
Minnesota, 6-145 Jackson Hall, 321 Church Street, Minneapolis, Minnesota 55455. E-mail: [email protected].
This work was supported by National Science Foundation
Grant IOS1025199.
Disclosure Summary: W.C.E. and J.M.Y. have nothing to
declare.
16.
17.
18.
19.
References
1. Rusak B, Zucker I 1979 Neural regulation of circadian rhythms.
Physiol Rev 59:449 –526
2. Moore RY 1983 Organization and function of a central nervous
system circadian oscillator: the suprachiasmatic hypothalamic nucleus. Fed Proc 42:2783–2789
3. Dallman MF, Engeland WC, Rose JC, Wilkinson CW, Shinsako J,
Siedenburg F 1978 Nycthemeral rhythm in adrenal responsiveness
to ACTH. Am J Physiol Regul Integr Comp Physiol 235:R210 –
R218
4. Jasper MS, Engeland WC 1994 Splanchnic neural activity modulates
ultradian and circadian rhythms in adrenocortical secretion in
awake rats. Neuroendocrinology 59:97–109
5. Ulrich-Lai YM, Arnhold MM, Engeland WC 2006 Adrenal splanchnic innervation contributes to the diurnal rhythm of plasma corticosterone in rats by modulating adrenal sensitivity to ACTH. Am J
Physiol Regul Integr Comp Physiol 290:R1128 –R1135
6. Engeland WC, Arnhold MM 2005 Neural circuitry in the regulation
of adrenal corticosterone rhythmicity. Endocrine 28:325–332
7. Dickmeis T 2009 Glucocorticoids and the circadian clock. J Endocrinol 200:3–22
8. Lilley TR, Wotus, Taylor D, Lee JM, de la Iglesia HO 2012 Circadian regulation of cortisol release in behaviorally split golden hamsters. Endocrinology 153:732–738
9. Swann JM, Turek FW 1985 Multiple circadian oscillators regulate
the timing of behavioral and endocrine rhythms in female golden
hamsters. Science 228:898 –900
10. de la Iglesia HO, Meyer J, Carpino Jr A, Schwartz WJ 2000 Antiphase oscillation of the left and right suprachiasmatic nuclei. Science
290:799 – 801
11. Ehrhart-Bornstein M, Hinson JP, Bornstein SR, Scherbaum WA,
Vinson GP 1998 Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev 19:101–143
12. Edwards AV, Jones CT 1987 The effect of splanchnic nerve stim-
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
ulation on adrenocortical activity in conscious calves. J Physiol 382:
385–396
Engeland WC, Gann DS 1989 Splanchnic nerve stimulation modulates steroid secretion in hypophysectomized dogs. Neuroendocrinology 50:124 –131
Ishida A, Mutoh T, Ueyama T, Bando H, Masubuchi S, Nakahara
D, Tsujimoto G, Okamura H 2005 Light activates the adrenal gland:
timing of gene expression and glucocorticoid release. Cell Metab
2:297–307
Bittman EL, Doherty L, Huang L, Paroskie A 2003 Period gene
expression in mouse adrenal tissues. Am J Physiol Regul Integr
Comp Physiol 285:R561–R569
Oster H, Damerow S, Kiessling S, Jakubcakova V, Abraham D, Tian
J, Hoffmann MW, Eichele G 2006 The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal
cortical clock. Cell Metab 4:163–173
Mahoney CE, Brewer D, Costello MK, Brewer JM, Bittman EL
2010 Lateralization of the central circadian pacemaker output: a test
of neural control of peripheral oscillator phase. Am J Physiol Regul
Integr Comp Physiol 299:R751–R761
Son GH, Chung S, Choe HK, Kim HD, Baik SM, Lee H, Lee HW,
Choi S, Sun W, Kim H, Cho S, Lee KH, Kim K 2008 Adrenal peripheral clock controls the autonomous circadian rhythm of glucocorticoid by causing rhythmic steroid production. Proc Natl Acad
Sci USA 105:20970 –20975
Fahrenkrug J, Hannibal J, Georg B 2008 Diurnal rhythmicity of the
canonical clock genes Per1, Per2 and Bmal1 in the rat adrenal gland
is unaltered after hypophysectomy. J Neuroendocrinol 20:323–329
de la Iglesia HO, Meyer J, Schwartz WJ 2003 Lateralization of
circadian pacemaker output: activation of left- and right-sided luteinizing hormone-releasing hormone neurons involves a neural
rather than a humoral pathway. J Neurosci 23:7412–7414
Kalsbeek A, Buijs RM, van Heerikhuize JJ, Arts M, van der Woude
TP 1992 Vasopressin-containing neurons of the suprachiasmatic
nuclei inhibit corticosterone release. Brain Res 580:62– 67
Kalsbeek A, Buijs RM, Engelmann M, Wotjak CT, Landgraf R 1995
In vivo measurement of a diurnal variation in vasopressin release in
the rat suprachiasmatic nucleus. Brain Res 682:75– 82
Buijs RM, Wortel J, Van Heerikhuize JJ, Feenstra MG, Ter Horst
GJ, Romij HJ, Kalsbeek A 1999 Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur J Neurosci 11:1535–1544
Swanson LW, Sawchenko PE 1983 Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev
Neurosci 6:269 –324
Delville Y, Stires C, Ferris CF 1992 Distribution of corticotropinreleasing hormone immunoreactivity in golden hamster brain. Brain
Res Bull 29:681– 684
Hastings MH, Herbert J 1986 Neurotoxic lesions of the paraventriculo-spinal projection block the nocturnal rise in pineal melatonin
synthesis in the Syrian hamster. Neurosci Lett 69:1– 6
Yan L, Foley NC, Bobula JM, Kriegsfeld LJ, Silver R 2005 Two
antiphase oscillations occur in each suprachiasmatic nucleus of behaviorally split hamsters. J Neurosci 25:9017–9026
Bradbury MJ, Akana SF, Dallman MF 1994 Roles of type I and II
corticosteroid receptors in regulation of basal activity in the hypothalamo-pituitary-adrenal axis during the diurnal trough and the
peak: evidence for a nonadditive effect of combined receptor occupation. Endocrinology 134:1286 –1296
Jones MT, Gillham B 1988 Factors involved in the regulation of
ACTH/␤-lipotropic hormone. Physiol Rev 68:743– 818