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Neuroendocrine Research Group, Department of Anatomy, University of Bristol School of Medical Sciences (R.J.W., S.A.W., C.D.I.), Bristol, United Kingdom BS8 1TD; and the Department of Medicine, University of Bristol, Bristol Royal Infirmary (R.J.W., S.A.W., N.S., S.L.L.), Bristol, United Kingdom BS2 8HW
Address all correspondence and requests for reprints to: Dr. Richard Windle, Neuroendocrine Research Group, Department of Anatomy, University of Bristol School of Medical Sciences, Bristol, United Kingdom BS8 1TD. E-mail: r.j.windle{at}bris.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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Some studies in rats suggest that pulsatile patterns of HPA activity are directly translated into an ultradian pattern of circulating corticosterone concentrations (11, 12). However, until recently, the constraints on blood collection imposed by the size of this species has made it difficult to measure the dynamic, stress-free patterns of hormone release over prolonged periods of time. In the present study we have employed an automated blood-sampling system that allows collection of small volumes of blood (13) to sample frequently over extended periods of time without stressing the animals. This has permitted an investigation of the patterns of corticosterone release over the whole 24-h cycle of the rat and has allowed us to directly address the hypothesis that pulsing represents short periods of active hormone secretion separated by periods of inhibition of the HPA axis. Two investigations related to this hypothesis have been undertaken: 1) to determine whether in the rat, pulses of corticosterone release are initiated throughout the light-dark cycle and whether differences in the frequency and/or magnitude of pulses make a significant contribution to circadian pattern of hormone release in this species (14, 15, 16, 17); and 2) if pulses are generated by alternate periods of hormone secretion and inhibition, to determine whether this has a variable influence on the responsiveness of animals to acute stress. Therefore, frequent sampling has been performed in conjunction with a short duration, mild white noise stress (18) to investigate the dynamic relationship between basal and stimulated HPA activities.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Jugular vein cannulation
Animals were anesthetized using a combination of Hypnorm (0.32
mg/kg fentanyl citrate and 10 mg/kg fluanisone, im; Janssen
Pharmaceuticals, Oxford, UK) and diazepam (2.6 mg/kg ip; Phoenix
Pharmaceuticals, Gloucester, UK). The right jugular vein was exposed,
and a SILASTIC-tipped polythene cannula (Dow Corning, Midland, MI; od,
0.96 mm; id, 0.58 mm; Portex, Hythe, UK) filled with 10 U/ml
heparinized isotonic saline was inserted into the vessel until it lay
close to the entrance of the right atrium. The free end of the cannula
was exteriorized through a scalp incision and then tunnelled through a
protective spring that was anchored to the parietal bones using two
stainless steel screws and self-curing dental acrylic. Once they had
recovered, animals were returned to their individual housing cages, and
the end of the spring was attached to a mechanical swivel that rotated
through 360° in a horizontal plane and 180° through a vertical
plane, giving the animals maximum freedom of movement. The cannulas
were flushed daily with the heparinized saline solution.
Automated blood sampling
Four days after surgery, the cannula of each animal was
connected to an automated sampling system, as previously described (13, 18). The system was activated at 1700 h, and the cannulas were
flushed with 10–20 µl heparinized isotonic saline every 60 min to
maintain patency until the start of sample collection. The animals were
left undisturbed until the end of the experiment.
Study 1: 24-h profile of corticosterone release
The collection of 10- to 20-µl blood samples commenced at
either 1800 h (n = 6) or 0600 h (n = 6) on the
fifth day after surgery and continued every 10 min for a 24-h period.
Two independent runs were conducted for each starting time. From a
second group of animals (n = 5), samples were collected every 5
min for a 4-h period commencing at 1800 h. The sampling system
then flushed the cannulas every 60 min until 0600 h on the
following day, when it automatically switched to the 5-min blood
collection protocol until 1000 h. Samples were collected at a 1:4
dilution in heparinized saline. The plasma fraction was separated by
centrifugation and used for the measurement of corticosterone
concentrations. Plasma pooled from samples collected between
0600–0700, 1200–1300, 1800–1900, and 0000–0100 h were used for
measurement of corticosterone-binding globulin (CBG)
concentrations.
Study 2: effect of noise stress on patterns of corticosterone
release
Blood samples for the determination of plasma corticosterone
were collected at 10-min intervals commencing at 0600 h on the
fifth day after surgery. After 140 min, a white noise generator was
activated, and the animals (n = 6) were exposed to 114 decibels
(12,000–60,000 Hz) for 10 min (18). Sampling continued for an
additional 320 min.
Study 3: relationship between basal corticosterone release and the
response to noise stress
To determine whether the pattern of basal corticosterone release
had any effect on the subsequent response to stress, a second, larger
group of animals (n = 26) underwent blood sampling and noise
stress as described above. Sampling continued for 120 min after the
stress. By studying only the prenoise corticosterone profiles, two
independent observers divided the animals on the basis of whether the
onset of the stress coincided with an active secretory (rising) or
inactive (falling) phase of a corticosterone pulse. Data were only
included in the subsequent analysis when there was agreement between
the two observers as to the pulse phase, and on this basis, two animals
were excluded. For analysis of the subsequent responses to stress,
these two groups were treated separately, and for each group the
responses were expressed as a percentage of the average baseline
corticosterone concentration.
Plasma clearance of corticosterone
To determine whether the profile of circulating corticosterone
levels seen could be due to short periods of release from the HPA axis,
groups of animals (n = 6) underwent bilateral adrenalectomy at the
time of cannulation. The drinking water of these animals was then
replaced with isotonic saline. Twenty-four hours later, a blood sample
(100 µl) was collected, and then each animal was injected iv with a
25-µg bolus of corticosterone in a volume of 0.1 ml followed by 0.2
ml isotonic saline (approximately twice the volume of the cannula).
Additional blood samples were collected at 1, 10, 20, and 30 min after
injection, in accordance with blood collection times from studies 1–3,
for the determination of plasma corticosterone and CBG levels. As the
presence of a constitutive amount of corticosterone could affect the
distribution of a bolus injection of the steroid or the circulating CBG
concentrations, a parallel group of animals was injected with the
corticosterone bolus after maintenance on drinking saline containing
250 mg corticosterone/liter.
Determination of plasma corticosterone concentrations
Total plasma corticosterone concentrations were measured
directly in plasma by RIA using a citrate buffer at pH 3.0 to denature
the binding globulin (4 µl diluted plasma fraction diluted in 100
µl buffer), antiserum supplied by Prof. G. Makara (Institute of
Experimental Medicine, Budapest, Hungary), and
[125I]corticosterone (ICN Biomedicals, Irvine, CA) with a
specific activity of 2–3 mCi/µg. The assay had a limit of detection
of 5 ± 1 ng/ml (n = 20), and intra- and interassay
coefficients of variation were measured at 12.4% and 16.0%,
respectively.
Determination of CBG concentrations
CBG levels were determined by single point assays. Plasma
samples (20 µl) were stripped of endogenous corticosterone using
freshly prepared LH-20 columns and eluted with 500 µl 30
mM Tris, 1 mM EDTA, 10 mM sodium
molybdate, 10% (vol/vol) glycerol, and 1 mM dithiothreitol
(TEDGM). Sample aliquots (150 µl) were incubated with a saturating
concentration (100 nM) of [3H]corticosterone
(total binding) or [3H]corticosterone and a 200-fold
excess of cold corticosterone (nonspecific binding). The bound and
unbound steroid were then separated by LH-20 chromatography at 4 C for
30 min. For each sample, triplicate determinants of total and
nonspecific binding were made by washing 100 µl of incubates into
columns with 100 µl TEDGM. The columns were eluted 30 min later with
500 µl TEDGM into scintillation minivials. Scintillation cocktail
(4.5 ml) was added to each sample and counted in a Packard
scintillation ß-counter (Packard, Downers Grove, IL) at 60%
efficiency. Protein content for the stripped aliquots was determined
using the Bradford method, and final values are expressed as picomoles
of [3H]corticosterone bound per mg protein.
Statistical analysis
The Pulsar analysis program was used to analyze pulse frequency,
height and amplitude, interpeak interval, and mean hormone
concentrations. The following G values were employed: G1 = 5,
G2 = 3.5, G3 = 2.5, G4 = 1.5, and G5 = 1.2,
together with a peak splitting parameter of 2 (SD units).
These values were obtained from visual inspection of the data as
recommended in the original method (19). Analysis of the data collected
from 20 replicates of 2 pooled plasma samples with mean concentrations
of 142 ± 5.4 and 25 ± 3 ng/ml corticosterone, detected 1
and 0 false peaks, respectively.
Values shown represent either individual datasets or the mean ± SE for groups. ANOVA with repeated measures and post-hoc Tukey’s tests were used to analyze differences in plasma corticosterone concentrations and CBG levels between defined periods of the 24-h cycle, to determine the effect of noise stress on corticosterone concentrations, and to determine the effect of pulse phase on the percent corticosterone response to noise stress. Paired Student’s t tests were used to compare plasma corticosterone concentrations, pulse frequency, interpeak interval, percentage of samples above baseline, and pulse height in animals sampled in the evening and the morning. Unpaired Student’s t tests were used to compare these pulse characteristics in animals that had been stressed with those in nonstressed controls. The corticosterone concentrations and CBG levels in adrenalectomized animals with or without corticosterone replacement and before and after iv corticosterone administration were compared by unpaired and paired Student’s t tests, respectively.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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; P
< 0.02, by ANOVA). Despite the clear variation in corticosterone
concentrations, circulating CBG concentrations did not vary
significantly over the 24-h period (Table 1). In addition to this
circadian rhythm, all rats showed a pulse-like ultradian pattern of
corticosterone release throughout the 24-h cycle (Fig. 1). The number of pulses was calculated
as 28 ± 2 over the 24-h period, giving a frequency of 1.15
± 0.07 pulses/h. The interpeak interval was calculated as 50.9 ±
3.7 min over the 24-h period, and 57.0 ± 4.57% of the values
were calculated to be above the baseline and so formed part of the
pulses.
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). This was further investigated in the group of
animals sampled at 5-min intervals during the evening (1800–2200 h)
and morning (0600–1000 h). As expected, the mean corticosterone
concentrations were significantly higher in the evening than in the
morning (Table 2; P <
0.05, by paired t test). The number of pulses, the interpeak
interval, and the percentage of samples above the calculated baseline
did not differ between the two times of the day (Fig. 2 and Table 2; by paired t
test). Pulse height was significantly greater in the evening than in
the morning (P < 0.05, by paired t test;
Table 2 and Fig. 2).
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). Although the magnitude of this
response varied from animal to animal (Fig. 3, B–D), it consistently
peaked 20 min after the onset of the noise when the mean plasma
corticosterone concentration reached 377 ± 87 ng/ml (Fig. 3A).
The corticosterone concentrations measured 20 and 30 min after
activation of the noise generator were significantly greater than those
measured at any time before stress (P < 0.05; Fig. 3A). Plasma corticosterone concentrations declined rapidly to reach or
fall below basal concentrations within 40–50 min. This response was
followed by a quiescent period before the generation of the next pulse,
and this gave an extended interpeak interval of 95 ± 9 min.
Although the magnitude of subsequent pulses did not exceed those
detected in the prestress period, quiescent periods were also seen
between these pulses (Fig. 3, B–D). Thus, when the period after the
noise stress was compared with the same period in nonstressed animals
from study 1, the number of pulses was significantly lower (5.6 ±
0.2 vs. 6.7 ± 0.3; P < 0.05), and the
interpeak was significantly longer (70 ± 3 vs. 48
± 2 min; P < 0.01).
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). Plasma corticosterone
concentrations peaked 20 min after the onset of the noise stress, when
they reached 602 ± 150% of the mean control value. In contrast,
when the noise stress coincided with a falling phase of the pulse (13
of 24 animals), the subsequent response was significantly smaller, with
plasma corticosterone levels not rising above the range of a basal
pulse (Fig. 4B). Two-way ANOVA showed that there was a significant
difference (P < 0.05) in the magnitude of the
corticosterone response to noise stress depending on the phase of the
pulse with which the stress was coincident (Fig. 4, A and B).
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and 2) or noise stress (Fig. 3), hormone
clearance was evaluated using our sampling frequency. Animals given
corticosterone replacement in the drinking saline had a mean
corticosterone concentration of 38 ± 11 ng/ml, which was similar
to that seen in intact animals at this time of day (Table 2), but
significantly higher than that in animals given saline alone to drink
(Fig. 5; P < 0.05). The
exogenous iv corticosterone bolus produced a mean plasma concentration
of 342 ± 93 ng/ml in these animals (Fig. 5B), similar to that of
the peak pulse amplitude (Fig. 1) or that evoked by noise stress (Fig. 3). The circulating corticosterone concentration fell to 84 ± 40
ng/ml within 10 min. This level was not significantly different from
the value before the bolus injection and indicated rapid clearance
(Fig. 5B). An estimated half-life of 8.6 ± 1.4 min was
calculated. Animals without corticosterone replacement in drinking
saline showed a similar pattern of corticosterone clearance after iv
injection (Fig. 5A). The CBG concentrations were not significantly
different between the two groups and were not affected by
corticosterone administration (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pulsatile activity of the HPA axis
Although not measured in these studies due to the limitations of
the frequent and prolonged sampling rate, ACTH release is known to
occur in a pulsatile manner in many species, including the rat (21, 22). The peptide shows the same circhoral rhythm and variation over the
24-h cycle (23). Similar observations regarding the release of CRF have
been made (24, 25). Therefore, the pulse-like pattern of corticosterone
release seen in the present studies probably represents pulsatility
throughout the HPA axis, and this is likely to be generated within the
central nervous system.
The production of pulse-like patterns of activity within the HPA axis
could involve rapid negative feedback of the corticosterone released
over the secretory phase of a pulse, which acts to inhibit CRF release
from the paraventricular nucleus. However, in vitro studies
using isolated hypothalami from macaque monkeys (26) have shown a
similar pattern of pulsatile CRF release in the absence and presence of
high dose glucocorticoids, suggesting that at least local negative
feedback is not involved. Furthermore, although yet to be confirmed in
the rat, this rhythmic release of CRF by the isolated hypothalamus (26)
shows that generation of the circhoral rhythm is an intrinsic property
of the hypothalamus. Although the generation of such endogenous rhythms
is often related to the suprachiasmatic nuclei, these nuclei were not
included in the macaque hypothalamic explants (26), and observations
that the pacemaker controlling sleep-wake patterns in the rat did not
control the ultradian rhythm of corticosterone release (27) suggest
that another structure is involved. An alternative explanation of pulse
generation may involve inhibitory ultrashort feedback within the
hypothalamus. However, as CRF itself is reported to have a stimulatory
effect on CRF-producing neurons in the paraventricular nucleus (28),
this feedback might involve an intermediate inhibitory factor, such as
-aminobutyric acid (29) or substance P (30, 31).
Contribution of pulse pattern to circadian rhythm of corticosterone
release
These data show that pulse-like episodes of corticosterone release
occurred equally over the entire 24-h cycle, as has been previously
observed in the human (3, 5, 6). Pulse frequency did not change over
the 24-h period, which indicates that any pulse-initiating mechanisms
that have influence over basal HPA activity have constant periodicity
throughout the day. This suggests that the HPA axis is actively driven
over the whole circadian cycle, although variations in this drive
result in the circadian profile of circulating corticosterone levels.
Such an observation is of fundamental relevance to HPA physiology, as
it is widely believed that the HPA axis is not actively driven during
the nadir phase of the circadian cycle. However, it is important to
note that complete cessation of secretory activity is indicated during
the interpulse period, when circulating corticosterone concentrations
fell to very low, often undetectable, levels. Thus, the major variable
in the pattern of corticosterone release over the 24-h period appears
to be the magnitude of the pulses, which also appears to be the case
for circadian ACTH release (23). Although the magnitude or duration of
individual CRF pulses may have varied over the 24-h period, it is also
possible that the efficacy of the CRF pulse on ACTH release may vary at
the level of the anterior pituitary. Indeed, it has been shown that
inhibition of glucocorticoid feedback increases both the magnitude and
the duration of ACTH bursts occurring in response to CRF pulses in the
human (32). As there is evidence that the sensitivity of the
corticotrophs to negative feedback of glucocorticoids varies over the
24-h period (33), this is a potential site for the variable control of
pulse magnitude during the day. Although the stage of the estrous
cycle, which might have influenced HPA function, was not taken into
consideration, all animals studied showed similar pulsatile patterns of
hormone release.
Dynamics of circulating corticosterone levels
In the studies reported here, the time taken for exogenously
injected corticosterone to be removed from the circulation of
adrenalectomized rats was very rapid, indicating that at the sampling
frequency employed (10 min), the dynamic patterns of hormone release
could be due to hormone release and removal from the circulation. This
removal appeared to occur in an exponential manner, which was similar,
although much faster, than that reported for the disappearance of
cortisol from the human circulation (10). The processes responsible for
this removal (metabolism, renal clearance, and distribution to
surrounding tissues) did not appear to have been affected by the lack
of endogenous corticosteroid in the adrenalectomized rat, as similar
clearance rates were seen after replacement of corticosterone to
physiological levels. Furthermore, the decline in corticosterone
concentrations after bolus injection is similar to the decay of
endogenous corticosterone pulses in the intact animals (e.g.
Fig. 2). This supports the suggestion that the ultradian rhythms of
corticosterone release represent short periods of active hormone
release followed by complete cessation of secretory activity and rapid
clearance of the circulating hormone.
Pulsatile release and rapid clearance of endogenous steroid mean that target tissues are exposed to very large fluctuations of free glucocorticoid, and like other hormones, this pulsatile presentation to target tissues may be an essential component of its biological action. Although the data shown here represent total circulating corticosterone, the concentration of CBG would be unlikely to change rapidly enough to counteract the dynamic fluctuations imposed by the pulsatile release of the hormone. Therefore, it is likely that similar fluctuations occur in the free steroid condition. We were unable to detect the previously reported rise in the concentration of CBG to compensate for the evening rise in circulating corticosterone concentrations (34). This suggests that the target tissues for the steroid would be exposed to greater variations in circulating free corticosterone during this part of the 24-h cycle.
Interaction between pulse pattern and HPA response to acute
stress
In agreement with earlier findings of the effects of white noise
(18, 35), noise stress evoked a transient increase in corticosterone
release that peaked 20 min after stress onset. The rate of decline in
corticosterone levels after this release was similar to the clearance
rate of the hormone, which suggested inhibition of the HPA axis.
However, as hormone levels fell below basal concentrations and remained
so for a period longer than the normal interpulse period, it is likely
that additional inhibitory mechanisms were involved. Such a
dissociation in the inhibitory control of basal and stimulated HPA
function is supported by observations that corticosterone release in
animals exposed to long term noise stress were chronically raised, but
pulse-like patterns of release, including regular periods of
inhibition, continued above this elevated baseline (36).
What is very evident from these studies is that the basal pulse pattern of corticosterone release had a profound effect on the response to noise stress. Animals only responded when the stress coincided with a rising or secretory phase of a pulse. When the stress fell on a falling phase of the pulses, which probably represents the period when the HPA axis is actively inhibited, no significant response was seen. This has obvious implications for the study of HPA physiology and, to our knowledge, is the first report of such an interaction. The reason that this has not been observed before may relate to the technical difficulty in measuring ultradian patterns of corticosterone release, but it is also probable that the more prolonged, intense stresses often employed, such as restraint or hypertonic saline injections (37), would mask the interaction, as they would have a greater probability of coinciding with the active secretory phase. This demonstration of a dynamic interaction between basal and stress-induced HPA activity involving periods when the axis does not respond to stress may have revealed an important factor determining the differential HPA responses to stress observed in individuals of different genetic strains or under different disease states.
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Acknowledgments |
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Footnotes |
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Received June 2, 1997.
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) and CBG
concentrations (
) before and after a 25-µg iv bolus of
corticosterone administered to adrenalectomized rats previously
maintained for 24 h on isotonic saline ad libitum
supplemented with 0 mg (A) or 250 mg (B) corticosterone/liter.