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Department of Biology, Imperial College of Science Technology and Medicine (R.J.L.), London, United Kingdom SW7 2AZ; School of Biological Sciences, University of Manchester (J.A.S., A.S.I.L.), Manchester, United Kingdom M13 9PT; and the Department of Biology, National Science Foundation Center for Biological Timing, University of Virginia (J.M.D., M.M.), Charlottesville, Virginia 22903
Address all correspondence and requests for reprints to: Dr. Andrew Loudon, School of Biological Sciences, Stopford Building, University of Manchester, Manchester, United Kingdom M13 9PT. E-mail: andrew.loudon{at}man.ac.uk
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A primary circadian oscillator in mammals is known to reside within the suprachiasmatic nuclei (SCN) (1, 2). The SCN generates a circadian rhythm both in vivo and in vitro, and specific lesions of these nuclei abolish both circadian activity and endocrine rhythms, demonstrating that they are essential for the temporal control of these processes (1, 2, 3, 4). Transplantation of fetal SCN tissue into SCN-lesioned hosts is capable of restoring rhythmicity in wheel-running behavior (5, 6). In Syrian hamsters, this restored rhythmicity has been unambiguously ascribed to rhythm generation within the donor SCN by transplantation of SCN tissue with a different endogenous period (7) from that of the donor animal. These findings have confirmed that a circadian clock controlling behavioral rhythmicity in mammals resides within the SCN. By contrast, SCN transplants have not been shown to restore endocrine rhythmicity to lesioned hosts. In nonmammalian vertebrates, the SCN is only one part of a circadian axis known to contain other autonomous oscillators (8). Recently, independent circadian oscillators have been discovered within the retinas of hamsters and mice, raising the possibility that other sites in the mammalian brain may contain circadian oscillators (9, 10). Thus, with respect to the circadian regulation of the endocrine axis, the possibility remains that the SCN fulfills a facilitatory, rather than primary, role in generating endocrine rhythms.
Here, we describe experiments using the circadian tau mutation in the Syrian hamster to examine the processes controlling circadian endocrine rhythmicity. This single autosomal mutation induces a reduction in the period of the circadian activity rhythm (11) from around 24 h in wild-type animals (tau++) to 22 h in the heterozygote (tauS+) and 20 h in the homozygous mutant (tauSS). A primary site of expression for the tau phenotype is known to be the SCN (7, 12, 13). In this study we examined the effect of the tau mutation on circadian endocrine rhythms (LH, melatonin, and cortisol) in animals maintained under free running conditions. Our results define clear circadian rhythms in plasma LH, melatonin, and cortisol concentrations in both tau++ and tauSS hamsters. These rhythms are synchronized with free running behavioral rhythms in both genotypes, suggesting a common period in these two axes, measured at around 20 h for tauSS and 24 h for tau++. The findings support the hypothesis that a tau-influenced circadian oscillator controls rhythmicity in these endocrine parameters.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exp 1
Plasma concentrations of melatonin, cortisol, and LH were
determined over the circadian cycle in tau++ and
tauSS hamsters to estimate the circadian period
and phasing of endocrine rhythms in the two genotypes. The validation
of a highly sensitive immunoradiometric assay for LH (14) allowed a
longitudinal sampling protocol (Exp 1b) to be employed for this
hormone, in which serial small volume blood samples were collected from
chronically cannulated animals. By contrast, the melatonin and cortisol
RIAs required relatively large volumes of plasma, which were collected
as single terminal samples in a cross-sectional protocol (Exp 1a). In
both cases, the collection of blood samples was timed relative to the
onset of wheel-running activity, defined as circadian time 12
(CT12).
a) Cross-sectional sampling protocol. Rhythmicity in melatonin and cortisol concentrations was determined from single terminal blood samples collected at different times over the entire circadian cycle from tau++ and tauSS hamsters. Female hamsters were bred under appropriate stimulatory photoperiods (12 h of light, 8 h of darkness for tauSS and 14 h of light and 10 h of darkness for tau++). At around 12 weeks of age they were bilaterally ovariectomized under halothane anesthesia. One week later, animals were transferred to individual cages under constant dim red light (<5 lux) with free access to a running wheel. Circadian wheel-running activity rhythms were monitored using a Dataquest III (Minimitter Co., Inc., Sunriver, OR) data acquisition system. It has previously been established that after 2 or more weeks of adaptation, prior photoperiod exposure has no significant influence on the pattern of melatonin production in hamsters (15). Consequently, animals were left for 18 full circadian cycles (15 and 18 calendar days for tauSS and tau++, respectively) in constant dim red light before sampling. At the end of that time, they were removed in dim red light and anesthetized (halothane), and a single terminal blood sample was collected in heparinized saline by cardiac puncture. Plasma was harvested and stored at -20 C before determination of melatonin and cortisol concentrations. Samples were collected from animals killed at intervals of 1 circadian h (i.e. 1/24 x period of circadian wheel-running rhythm) over the entire circadian cycle. For each animal, activity onset (CT12) on the day of sampling was estimated with reference to activity onsets for the preceding seven circadian cycles. Circadian times for sampling were then calculated using CT12 as a reference point. Between four and eight animals were sampled per genotype at each time point.
b) Longitudinal sampling protocol. Sequential small volume
blood samples were collected from individual, freely moving animals for
determination of rhythms in LH concentrations. Female hamsters (8
tau++, 11 tauS+, and 13
tauSS) housed under appropriate stimulatory
photoperiods (14 h of light, 10 h of darkness for
tau++; 12.8 h of light, 9.2 of darkness for
tauS+; 11.7 h of light, 8.3 h of darkness for
tauSS) were bilaterally ovariectomized under
pentobarbital anesthesia at around 10 weeks of age. After a further 2
weeks, animals were anesthetized with pentobarbital and fitted with an
indwelling atrial cannula, as described previously (16), to enable
subsequent remote collection of small blood samples. The external
portion of the cannula was filled with heparinized (15 U/ml) sterile
0.9% saline solution. Animals also received sc 5-mm SILASTIC brand
implants (Dow Corning, Midland, MI) filled with ß-estradiol
3-benzoate at this stage to induce daily LH surges (17). Animals were
subsequently housed singly in constant white light (100–400 lux) with
free access to a running wheel linked to a Dataquest IV (Minimitter Co.
Inc.) data acquisition system, from which circadian activity rhythms
were monitored. After four circadian cycles, a series of 25-µl blood
samples were taken from each animal over the course of one or two
cycles. At each sample, the volume of blood was replaced with
heparinized saline solution (15 U/ml). Only a moderate decrease in
hematocrit readings was observed between the first and last samples
taken from each animal (range, 0–12% reduction). Sampling was timed
with respect to the observed activity rhythm of each animal, such that
samples were taken every 0.5 circadian h over the course of the
subjective afternoon (CT4 to CT12) when the LH surge was predicted to
occur and less frequently (1–3 circadian h between samples) over the
rest of the circadian cycle. Animals remained undisturbed during the
process of blood sample collection, and their behavior was appropriate
for that phase of the circadian cycle. Activity rhythms were monitored
for 2–3 days after sampling was discontinued. There was no significant
phase shift in the activity rhythm in response to the sampling protocol
(see Fig. 2a
). Plasma was harvested from the blood samples and assayed
for LH.
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Hormone assays
Melatonin. Two melatonin RIAs were used in this study.
Concentrations of melatonin in extracted plasma (Exp 1) were measured
using the only currently validated RIA available for the measurement of
melatonin in hamster plasma/serum (19). As previously described (19),
plasma samples were extracted in dichloromethane, dried down, and
reconstituted in assay buffer for subsequent assay using a double
antibody RIA. The primary antiserum was raised against melatonin in the
rabbit (Stockgrand Ltd., Guildford, UK), and the resultant
antibody-hormone complex was precipitated using ferric-bound second
antibody (donkey antirabbit; supplied by Prof. Lynch, Department of
Clinical Biochemistry, Birmingham Women’s Hospital, Birmingham, UK).
Competition was provided by radiolabeled melatonin
(2-[125I]iodomelatonin, Amersham), and samples were
compared against a commercially available melatonin standard
(Sigma Chemical Co.). The minimum detectable melatonin
concentration was 9.7 pg/ml, and the intra- and interassay coefficients
of variation for repeated determinations of plasma pools at 15.9 and
172.2 pg/ml were 39% and 7% (intraassay) and 34% and 11%
(interassay). Plasma samples were assayed in duplicate.
The melatonin concentration in culture medium (Exp 2) was determined using a direct RIA, as described by Fraser and co-workers (20). Sheep antimelatonin antiserum was obtained from Stockgrand Ltd. (Guildford, UK), and bound melatonin was separated using dextran T-70-coated activated charcoal (Sigma Chemical Co.). Competition was provided by radiolabeled melatonin ([3H]melatonin, Amersham), and samples were compared against a melatonin standard (Sigma Chemical Co.). This assay was validated for use with culture medium by demonstrating parallelism of serial dilutions of standard and culture medium over the 10–200 pg/ml range (data not shown). All samples were run in duplicate within a single assay. The minimum detectable melatonin concentration was 10 pg/ml, and the intraassay coefficients of variation at 72 and 163 pg/ml were 4.3% and 2.3%, respectively.
Cortisol. Plasma cortisol concentrations were measured using a double antibody enzyme-linked immunosorbant assay on samples extracted with dichloromethane. The protocol used was an adaptation of that described by Cooper and co-workers (21) and previously validated for use in Syrian hamsters (22). A polyclonal anticortisol antibody raised in rabbits (Cambio, Cambridge, UK) was employed, and a secondary goat antirabbit IgG antibody (ICN ImmunoBiologicals, Irvine, CA) was used to bind the antibody-hormone complex to the walls of a Nunc Maxisorp Immuno-Plate (Life Technologies). Competition was provided by a hydrocortisone peroxidase conjugate (Sigma Chemical Co.), and the quantity of conjugate bound was estimated by an OD measurement after a 1,1'-trimethylene-bis(4-formylpyridium)dioxine (Sigma Chemical Co.) reaction. The intra- and interassay coefficients of variation for plasma pools at 350 and 4047 pg/ml were 9.9% and 5.6% (intraassay) and 14.7% and 13.3% (interassay). Plasma samples were assayed in duplicate.
LH. A two-site sandwich immunoradiometric assay [as described by Fallest and co-workers (14)] was performed on plasma samples to determine LH concentrations. In the presence of LH, a radiolabeled (125I) monoclonal antibody specific to the ß-subunit of human LH (no. 5303, Medix, Kaunianen, Finland) was immobilized to an avidin-coated polystyrene bead (7 mm in diameter; Nichols Institute Diagnostics, San Juan Capistrano, CA) by a biotinylated monoclonal LH antibody (Dr. J.Roser, University of California-Davis). Samples were compared against standards of known concentration (RP-3, NIDDK). The limit of detection for this assay was 0.04 ng/ml. Intra- and interassay coefficients of variation were 4–9%. The small quantity of blood collected at each time point meant that samples could not be assayed in duplicate. To avoid interassay variations, all samples from a single animal were assayed in series within a single assay.
Statistical analysis
Within each genotype, one-way ANOVA was used to test for
circadian rhythmicity for each endocrine system. Two-way ANOVA was
employed to test for overall differences in circadian rhythmicity
between genotypes. Detailed examination of the rising (CT15–19) and
falling (CT22–2) phases of melatonin production were carried
out using two-way ANOVA comparing genotypes to test for differences in
the timing of these two specific events. A detailed analysis of the
phasing and amplitude of the LH surge in the three genotypes was also
carried out as follows. The mean circadian phasing of the LH surge in
each individual was estimated as the CT of maximal LH concentrations
and compared between genotypes using a one-way ANOVA. The amplitude of
the surge was assessed by estimating the total quantity of LH released
during the surge (measuring the area under the curve) and by
calculating the peak to trough concentration of LH for each animal. The
area under the curve data were analyzed using a one-way ANOVA for
comparison between genotypes, with post-hoc Student-Newman
Keuls tests. In contrast, the peak to trough data violated the
assumption of normality and consequently were analyzed using the
nonparametric Kruskal-Wallis one-way ANOVA, with post-hoc
Dunn’s tests. Statistical significance was defined as
P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exp 1a
Melatonin. There was a significant circadian variation in the
plasma concentration of melatonin in both tau++
(P < 0.001; one-way ANOVA) and
tauSS (P < 0.001, by one-way
ANOVA) hamsters (Fig. 1A). The melatonin
rhythms were broadly similar in the two genotypes, with basal
concentrations over much of the subjective day (inactive phase of the
wheel-running rhythm) and elevated secretion over the latter part of
the subjective night (active phase). Two-way ANOVA failed to reveal a
significant effect of genotype on the overall melatonin profile
(P > 0.05). Inclusion of all times at which melatonin
concentrations are either basal or peak makes the two-way ANOVA
insensitive to differences at the two key phases of melatonin rise and
fall. Detailed examination at these phases of the cycle indicated that
melatonin concentrations rose significantly earlier in
tauSS than in tau++
hamsters (by two-way ANOVA restricted to CT15–19, effect of genotype,
P < 0.05). In contrast, the timing of the decline in
melatonin concentrations was not significantly different (by two-way
ANOVA restricted to CT22–2, effect of genotype,
P > 0.05).
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). There was a high degree of interindividual
variation in the concentrations of this hormone, although both
tau++ and tauSS exhibited
a trend for cortisol concentrations to reach a nadir around CT0.
However, two-way ANOVA failed to detect any differences in the
circadian profiles between the two genotypes (P >
0.05).
Exp 1b
LH. After cannulation, all animals exhibited clear circadian
rhythmicity in wheel-running behavior under constant dim white light
(100–400 lux; Fig. 2A). In each case the
quality of the activity rhythm was sufficient to indicate a clear time
for activity onset (CT12). The tauSS,
tauS+, and tau++ hamsters
exhibited conspicuous circadian rhythmicity in plasma concentrations of
LH, with all but 1 of the 32 animals sampled over the subjective
afternoon on the fourth cycle in constant light (13
tauSS, 11 tauS+, and 8
tau++) exhibiting a discrete LH surge lasting
approximately 2 h (Fig. 2B and Table 1). In all three genotypes, LH
concentrations were basal throughout the remainder of the cycle (Fig. 3, A–C). When blood sampling was
extended to cover consecutive circadian cycles (n = 2
tauSS, 2 tauS+, and 1
tau++), LH surges were observed on the
subjective afternoon of both cycles. The period between consecutive LH
surges (20 and 20.7 h for tauSS; 22.5 and
23 h for tauS+, 24.1 h for
tau++) was similar to the period of the activity
rhythm (see below) in these genotypes (Fig. 4).
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), nor was the overall duration of the surge (P
> 0.05, by one-way ANOVA; Table 1). However, there was a significant
effect of genotype on the amplitude of the LH surge, as defined either
by the area under the curve (Table 1; P < 0.05, by
one-way ANOVA) or as the peak to trough difference (mean ±
SEM, 2.8 ± 0.62 pg/ml tauSS,
4.8 ± 2.0 pg/ml tauS+, and 6.9 ±
0.96 pg/ml tau++; P < 0.05, by
Kruskal-Wallis one-way ANOVA on ranks). Post-hoc
Student-Newman-Keuls (for estimates of total LH released) and Dunn’s
tests indicated that the surge amplitude was significantly reduced
(P < 0.01) in tauS+ compared
with tau++, but was not significantly
(P > 0.05) different between
tauSS and tau++ or
between tauSS and tauS+
animals. Activity rhythms. The period (mean ± SD) of free running circadian activity rhythms for wild-type and tau mutant hamsters was similar to previous reports (11) under both cross-sectional (Exp 1a, 20.11 ± 0.17 h for tauSS and 23.96 ± 0.11 h for tau++) and longitudinal (Exp 1b, 19.91 ± 0.21 h for tauSS, 21.83 ± 0.16 for tauS+, and 23.92 ± 0.15 h for tau++) sampling protocols.
Exp 2
Norepinephrine stimulation in vitro induced a large
(
5-fold) increase in melatonin production in both the
tau++ and tauSS pineal
cultures (Fig. 5). The amplitude and time
scale of response were similar in both genotypes. Before norepinephrine
administration, cultured pineals released melatonin into the culture
medium at a rate of around 15–40 pg/gland·h. After the addition of
norepinephrine, melatonin production remained around this level for an
additional 5–6 h in both tau++ and
tauSS. Melatonin then increased over the next
3 h in both genotypes. At this point the rate of melatonin
production varied from 80–250 pg/gland·h. In the absence of
norepinephrine, pineal cultures did not exhibit any such change in
melatonin production over the course of the experiment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Collecting blood samples at set phases of the circadian activity rhythm, we have described rhythmicity in circulating concentrations of LH, melatonin, and cortisol in wild-type and tau mutant hamsters. The relatively large volumes of plasma required for the melatonin and cortisol assays preclude a direct assessment of circadian period in these rhythms by serial sampling of individual animals over several cycles. However, the presence of clear rhythmicity in melatonin, cortisol, and LH when individual samples obtained from free running hamsters are pooled with respect to concurrently measured activity rhythms indicates that activity and endocrine rhythms are synchronized, exhibiting the same period. Consequently, these data demonstrate that, in common with behavioral rhythms, the periodicity of endocrine rhythms is reduced to around 20 h in tauSS and 22 h in tauS+. This observation was confirmed by the measurement of consecutive LH surges at intervals approaching 20 and 22 h from individual tauSS and tauS+ hamsters.
Chronically ovariectomized females from all three genotypes (tauSS, tauS+, and tau++) exhibited significant surges in LH release when treated with ß-estradiol 3-benzoate. LH surges were restricted to the subjective afternoon, with the mean time of maximal LH concentrations around CT7 in all genotypes. This is similar to that previously recorded for similarly treated tau++ hamsters free running in constant light (23, 24, 25) and indicates that the phasing of the LH surge is unaffected by the tau mutation. At all other phases of the circadian cycle, LH concentrations were basal. Similarly, cortisol concentrations in both tauSS and tau++ hamsters showed significant circadian rhythmicity, with maximal titers in the late subjective afternoon, preceding activity onset (CT12), and minimal titers towards the end of the subjective night (around CT0). Stress associated with blood collection may have blunted the circadian responses, but our data show phasing consistent with previous reports for tau++ hamsters (26, 27).
The circadian melatonin rhythm observed in tau++ hamsters in this study was similar in both phasing and amplitude with a previously published report for wild-type animals maintained under similar conditions (19). In both tau++ and tauSS, melatonin concentrations were significantly elevated over the latter portion of the subjective night and basal throughout the remainder of the cycle. However, although the overall phasing of melatonin secretion was similar in both genotypes, the initial increase in melatonin concentrations occurred significantly earlier in tauSS (CT15–18 vs. CT17–19) with the consequence that plasma melatonin concentrations were elevated for a greater portion of the circadian cycle in this genotype. We cannot rule out the possibility that this effect reflects differences in the strain background (tauSS, Charles River; tau++, Wright’s) of the hamster colonies used for this part of the study. However, we consider this to be unlikely. A previous examination of melatonin profiles in hamsters from these two colonies (19) failed to detect a difference in either the phasing or amplitude of the melatonin rhythm. Moreover, the phasing of the rise in melatonin production reported here for Wright’s tau++ is similar to that previously reported for Charles River tau++ under similar conditions (19).
There is extensive evidence that the regulation of the rise and decline in melatonin secretion in early and late night is under independent control. The phase relationship between these two events is altered according to the photoperiod (19, 28, 29), and appropriate stimuli are capable of resetting the phase of one of these events independently of the other (30, 31). The circadian phasing of the rise and decline in pineal melatonin production with respect to the activity rhythm is under similarly complex control. Previous studies of wild-type hamsters have shown that although the time from activity onset to the decline in melatonin concentrations varies according to photoperiod, the duration between activity onset and the increase in melatonin production is strictly maintained (19, 28, 29). This phase relationship remains fixed even in circumstances in which animals are reentraining to new photoperiods (15, 28, 29). These reports, confirming that the circadian phasing of the melatonin rise is strictly maintained relative to activity onset, suggest that our observation of a phase advance in this event in tauSS reflects a reproducible alteration in circadian outputs by the tau mutation rather than a transient effect of preexperimental environment.
The temporal control of pineal melatonin production is complex, involving circadian input from the hypothalamus and time-dependent local processes within the pineal gland. Principally, the circadian production of melatonin is driven via a multisynaptic stimulatory pathway originating in the hypothalamus, which induces trans-synaptic release of norepinephrine at the pineal (32), and consequent regulation of N-acetyltransferase, the rate-limiting step in melatonin synthesis (33, 34). In many species, the nocturnal increase in melatonin concentration is nearly coincident with the onset of darkness, but in the Syrian hamster there is a 5- to 6-h delay between these two events. This phase relationship is not consequent upon a delay in activation of the norepinephrine pathway, because a similar time period is required before the pineal responds to exogenous noradrenergic stimulation in vivo (35) or in vitro (18). Instead, the phase delay appears to be a product of intracellular time-dependent processes within the pinealocyte, including de novo protein synthesis (36). Consequently, the circadian pattern of pineal melatonin production, although driven by timed norepinephrine stimulation, is also modulated by time-dependent local processes.
The complexity in control of pineal melatonin production allows two general explanations for the phase advance of melatonin production observed in tauSS in vivo. 1) The circadian activation of norepinephrine release at the pineal is advanced in tauSS relative to tau++. 2) The pineal gland of the tau mutant hamster responds more rapidly to norepinephrine. The results of our study (Exp 2) demonstrate clearly that at least at the norepinephrine concentration used here, explanted pineal glands take the same time to show a significant response to norepinephrine stimulation regardless of genotype. Consequently, we conclude that the phasing of norepinephrine release is probably advanced in tauSS relative to the circadian activity rhythm. Thus, the phase advance in the onset of melatonin production is more likely to reflect a disruption of central rhythm generation processes by the tau mutation, rather than local action within the pinealocyte.
Pineal melatonin plays a central role in the regulation of seasonal breeding (37, 38). Syrian hamsters are strongly seasonal breeders and remain reproductively active under long day lengths (photoperiods): short night lengths (scotoperiods). Under stable entrainment to light-dark cycles, the phase of pineal melatonin production acts as an internal representative of scotoperiod driving seasonal responses by expanding and contracting to reflect the duration of the dark phase. Experimental manipulations of scotoperiod have confirmed that (male) tau mutant hamsters are capable of exhibiting appropriate seasonal responses and undergoing testicular regression when such light-dark cycles are presented in a 20-h rhythm (39, 40). However, the reproductive axis of tauSS exhibits photoperiodic responses (i.e. testicular regression) to scotoperiods that are 1–2 h shorter than those required by tau++. As a result, they require exposure to absolutely fewer hours of darkness per circadian cycle to exhibit reproductive collapse. Our current results suggest a possible explanation, as elevated melatonin concentrations may extend over a greater proportion of the dark phase in tauSS than tau++, with the result that a short day physiological response is generated on a photoperiod that does not cause reproductive inhibition in wild types (39).
The tau mutation was first identified as a shortening of the period of circadian wheel-running rhythms to around 22 h in tauS+ and 20 h in tauSS (11). Since then, 20-h rhythms in body temperature (41), electrical activity within the SCN (12, 13), photoreceptor disk shedding (42), and retinal melatonin synthesis (9) have been described in tauSS hamsters. Here we demonstrate approximately 20-h circadian rhythms of LH, melatonin, and cortisol in tauSS. Together, these findings provide compelling evidence that the period of the entire circadian axis is reduced by this single gene mutation. The tau mutation thus offers an ideal model to examine the extent to which single dominant or multiple circadian oscillators drive neuroendocrine pathways and even whether such oscillators are an ubiquitous feature of most cell types (43).
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Acknowledgments |
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Footnotes |
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Received April 6, 1998.
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