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Neuroendocrine Research Group, Department of Anatomy, 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., S.L.L.), Bristol, United Kingdom BS2 8HW
Address all correspondence and requests for reprints to: Dr. Richard Windle, Department of Anatomy, School of Medical Sciences, University of Bristol, University Walk, Bristol, United Kingdom BS8 1TD. E-mail: r.j.windle{at}bris.ac.uk
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Through the wide ranging actions of glucocorticoids on the central nervous system, immune tissues, and metabolic processes, variations in the basal activity of the HPA axis as well as the responsiveness of the axis to stress could influence the susceptibility to or the severity of a number of diseases. One animal model that has been extensively studied in this respect is the Lewis rat. This strain is susceptible to a range of inflammatory conditions, including streptococcal cell wall-induced arthritis (10, 11, 12, 13) and experimentally induced encephalomyelitis (14, 15). However, the closely related, histocompatible Fischer rat does not develop any of these conditions (11, 12, 13). This differential susceptibility has been linked to differences in HPA activity between the two strains. Generally, the Lewis rat displays a markedly smaller HPA reaction to a wide range of physical (16, 17), psychological (16, 17, 18, 19, 20, 21, 22, 23, 24), and immunological (13, 17, 24, 25, 26) stresses compared with the Fischer rat. It has been suggested that the reduced level of corticosterone released by the Lewis rat is insufficient to terminate inflammatory responses, and as a result, they show an increased susceptibility to autoimmunity (11, 12, 13, 15). Resolving the mechanisms underlying the differential regulation of HPA function in these two strains could therefore produce important information concerning the pathogenesis of these diseases. Thus, we investigated the ultradian patterns of basal HPA function, their relationship to stress responsiveness, and how this might contribute to altered HPA function in these two strains.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Jugular vein cannulation
Animals were anesthetized with halothane delivered in a mixture
in nitrous oxide and oxygen. The right jugular vein was exposed, and a
SILASTIC (Dow Corning, Midland, MI)-tipped polythene cannula (od, 0.96
mm; id, 0.58 mm; Portex, Hythe, UK) filled with heparinized (10 U/ml),
pyrogen-free, 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 recovered,
animals were returned to their individual 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.
Study 1: 24-h profile of corticosterone release in Lewis and
Fischer rats
Four days after surgery, the cannula of each animal was
connected to an automated sampling system as previously described (9, 27, 28). The system was activated at 1700 h, and the animals were
then left totally undisturbed until the end of the experiment. The
cannulas were initially flushed with 10–20 µl heparinized isotonic
saline every 60 min to maintain patency until the start of sample
collection. The collection of 10- to 20-µl blood samples commenced
either at either 1800 or 0600 h on the fifth day after surgery and
continued every 10 min for a 24-h period. 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. The experiment consisted of four individual runs, and
each consisted of equal numbers of Lewis and Fischer rats.
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 120 min, a white noise generator was
activated, and both Lewis (n = 13) and Fischer (n = 11) rats
were exposed to 114 dB (12–60,000 Hz) for 10 min (9, 28). Sample
collection then continued for an additional 240 min. By studying the
prenoise corticosterone profiles, the secretory status of each animal
at the onset of the noise was categorized on the basis of whether the
onset coincided with an active secretory (rising) or an inactive
(falling) phase of a corticosterone pulse, as previously described (9).
Throughout this study the behavior of each animal was recorded on
videotape.
Study 3: effect of CRF injection on plasma 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 120 min, Lewis (n = 6) and Fischer
(n = 7) rats were given an iv injection of 2 µg CRF in 0.2 ml
isotonic saline. The injection was timed to coincide with the stage of
the sampling cycle when saline was being returned to the animals. The
apparatus was arranged so that the injection could be given remotely
from the animals through a side arm of the system. Sampling then
continued for an additional 120 min. As in study 1, by studying the
preinjection corticosterone profiles, the individual responses of
animals from each strain of rat were categorized on the basis of
whether the injection coincided with an active secretory (rising) or an
inactive (falling) phase of a corticosterone pulse.
Measurement of plasma corticosterone
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 12.4% and 16.0%, respectively.
Behavioral analysis
The video recordings collected during the noise stress study
were divided into 10-min blocks, using the start of the noise stress as
the reference point. For each 10-min block, the amount of time that the
animals spent actively engaged in activities such as locomotion,
burrowing, or grooming (total activity) was recorded along with the
number of rearings (defined as the raising of both forepaws and
movement of body to a vertical plane). Grooming activity was also
analyzed separately as a measure of displacement behavior.
Statistical analysis
The values shown represent either individual datasets or the
mean ± SE for groups. The PULSAR analysis program
(29) was used to analyze pulse frequency, height, interpeak interval,
and mean hormone concentrations over the 24-h period. 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 for the original method (29).
Application of these values to 20 replicates of 2 pooled plasma samples
with mean concentrations of 142 ± 5 and 25 ± 3 ng/ml
corticosterone detected only 1 and no false peaks, respectively. For
determination of circadian variations in pulse characteristics, the
24-h profile for each animal was divided into 4 6-h periods. PULSAR
analysis was carried out separately on each of these periods. ANOVA and
post-hoc Tukey’s tests were used to compare pulse
characteristics over the 24-h cycle, and pulse characteristics were
compared between strains using Student’s t tests.
In response to noise stress, circulating corticosterone concentrations were considered significantly elevated only if they were significantly higher than the mean hormone levels measured at any time during the basal period. The integrated responses were calculated as the average increase in hormone levels above the averaged baseline for the 1-h period after the onset of the stress or CRF injection. ANOVA and post-hoc Tukey’s test were used to compare corticosterone levels between control and experimental periods, between strains, and between the responses occurring when stress coincided with a rising or falling phase of a pulse; to determine the effect of CRF injection on circulating corticosterone levels; and to analyze the behavioral responses to noise stress.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and Fischer
rats (Fig. 2) showed discrete pulses of
corticosterone release throughout the 24-h cycle, with peak levels
reaching as much as 400 ng/ml and interpulse concentrations falling to
below the limit of detection of the assay (<5 ng/ml). These pulses
occurred at an approximately circhoral frequency, with the average
number of pulses over the 24-h period being similar between Lewis
(29 ± 1; Fig. 1) and Fischer (28 ± 1; Fig. 2) rats. In the
Lewis rat, the mean circulating corticosterone concentration showed a
characteristic circadian variation (by ANOVA, P <
0.001; Fig. 3A), being highest at the
beginning of the dark phase and lowest at the beginning of the light
phase. This was due to cyclical variations in both the frequency and
the amplitude of the corticosterone pulses (Table 1). The frequency with which pulses of
corticosterone release occurred was significantly greater and,
inversely, the interpulse interval was shorter in the evening than in
the morning (P < 0.005; Table 1). Secondly, the height
of the pulses was significantly higher in the evening, being nearly
twice the morning value (P < 0.03; Table 1 and Fig. 1). In contrast to the Lewis rat, Fischer rats showed no significant
variations in either pulse frequency or pulse height over the 24-h
period (Table 1 and Fig. 2). Consequently, mean circulating
corticosterone levels remained relatively constant throughout the day
(Table 1 and Fig. 3B). The lack of an early morning trough of
corticosterone release in the Fischer rat was the most obvious
distinguishing difference from the Lewis strain (Fig. 3 and Table 1).
This was due to the significantly greater pulse heights in the Fischer
rats during this quarter of the 24-h period (Table 1).
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). This consistently reached a peak 20
min after the onset of the noise, with a group mean corticosterone
concentration of 237 ± 67 ng/ml, before declining rapidly to
reach the basal level 50 min later and undetectable levels at 60 min.
This response, however, depended on the phase of the corticosterone
secretion cycle at the onset of noise stress (Fig. 4, B and C;
P < 0.02). When the application of the noise stress
coincided with a rising phase of a pulse, a large increase in plasma
corticosterone concentrations was observed (Figs. 4B and 5A), achieving
mean peak levels of 323 ± 97 ng/ml. Plasma corticosterone
concentrations measured 20 and 30 min after the onset of the noise were
significantly greater than all basal values measured before the noise
stress. However, when the noise stress coincided with a falling phase
of the pulse (e.g. Fig. 5B),
no significant increase in the group mean corticosterone concentration
was observed (Fig. 4C). Consequently, the integrated response to noise
stress was significantly greater when noise stress coincided with a
rising phase of a pulse than when it coincided with a falling phase
(70 ± 16 vs. 14 ± 21 ng/ml, respectively;
P < 0.05).
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),
corresponding to the lack of the early light phase trough seen in study
1. As in the Lewis rat, noise stress caused an abrupt rise in plasma
corticosterone concentrations in Fischer rats, which peaked 20 min
after the onset of the stress at 390 ± 57 ng/ml (Fig. 6A).
However, unlike those in the Lewis rat, plasma corticosterone
concentrations did not fall abruptly, but remained maximally elevated
for an additional 20 min (Fig. 6A). Thus, the overall integrated
response to noise stress was significantly greater in these animals
(Fischer, 162 ± 34 ng/ml; Lewis, 50 ± 16 ng/ml;
P < 0.01). Furthermore, in complete contrast to that
in the Lewis rat, the response to noise stress in Fischer rats was not
influenced by the underlying pulse pattern of corticosterone release.
Noise stress elicited a similar significant response regardless of
whether it coincided with a rising phase (Figs. 5C
and 6B) or a falling
phase (Figs. 5D and 6C) of a basal corticosterone pulse. Thus, the peak
corticosterone response and its duration were comparable between the
two subgroups, and this was reflected in similar integrated
corticosterone responses (rising group, 175 ± 57; falling group,
145 ± 42 ng/ml).
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). This was associated with a similar
large increase in specific anxiety-related behaviors, such as rearings
(Fig. 7C), and displacement activities, such as grooming (Fig. 7B) and
burrowing. Indeed, for over 30% of the 10-min period during the noise
stress these animals were grooming. In contrast to the Fischer rats,
Lewis rats showed no significant increase in either total activity
(Fig. 7A) or grooming activity (Fig. 7B) during the noise stress,
although both activities did increase during the poststress period to
levels similar to those seen in the Fischer rats. The absolute number
of rearings did increase during the noise stress in the Lewis rat, but
was significantly less than that in the Fischer rats (Fig. 7C).
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). The response was very rapid in
Fischer rats, reaching a peak of 473 ± 95 ng/ml at 10 min (Fig. 8B). In contrast, the Lewis rat showed a more gradual increase in
corticosterone levels, which did not reach a peak level (390 ± 75
ng/ml) until 30 min after the CRF injection (Fig. 8A). Corticosterone
concentrations remained elevated for at least 60 min in both strains of
rats, and over this period the integrated corticosterone response to
CRF did not differ between the two strains (Fischer, 197 ± 49
ng/ml; Lewis, 210 ± 23 ng/ml). Furthermore, unlike the response
to noise stress in the Lewis rat (study 2), the integrated
corticosterone responses to CRF injection were similar between those
animals in which injection coincided with a rising phase of the pulse
and those in which it coincided with a falling phase of the pulse
(Lewis rat: rising group, 209 ± 67; falling group, 217 ± 66
ng/ml; Fischer rats: rising group, 189 ± 43; falling group,
235 ± 36 ng/ml).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Strain differences in pulsatile HPA activity and its contribution
to the circadian rhythm of corticosterone release
In both Lewis and Fischer rats, corticosterone release occurred in
a series of discrete pulses throughout the 24-h period with a circhoral
rhythm. This pattern of secretion is similar to the pulsatile
corticosteroid secretion that has previously been reported in male (6, 7) and female (9) Sprague-Dawley and male Wistar (8) rats and that is
also seen in other species (1, 2, 3, 4, 5, 30, 31, 32, 33). The characteristics of
individual pulses were such that the peak corticosterone levels were
often very high for basal samples, although after the peak these levels
fell rapidly until they were undetectable. Thus, body tissues would be
continuously exposed to very widely fluctuating corticosteroid
concentrations, a fact often overlooked in considering the effects of
and mechanisms regulating HPA function.
Although corticosterone secretion may be modulated by sympathetic innervation at the level of the adrenal gland (7), the pulses of secretion are generated at the hypothalamo-pituitary level and are driven by ultradian patterns of ACTH release. Ultrashort pulses of ACTH, lasting a few minutes (34) and produced partly by intrinsic rhythmicity of the corticotrophs (35), have been detected. However, circhoral pulses of ACTH similar to the glucocorticoid pulses have also been seen (2, 4, 30, 34, 35), and these are most likely to be generated at the level of the hypothalamus. Indeed, CRF does show an ultradian pattern of release (36, 37, 38). This in itself is partly intrinsic to the hypothalamus (39). Thus, the pulsatile patterns of corticosterone release probably arise within the central nervous system, but are also likely to involve modification throughout the HPA axis.
To our knowledge this is the first study of Fischer and Lewis rats characterizing the HPA axis in undisturbed, chronically catheterized animals. Many previous studies have collected blood samples either by cutting the tail vein (19, 40) or by decapitation (13, 16, 20, 22, 25, 41, 42, 43, 44). As both of these procedures involve some degree of handling, which could have a significant effect on plasma corticosterone levels, this may explain the discrepancies in these reports. Morning corticosterone levels in female Fischer and Lewis rats have been reported either not to differ between the two strains (16, 20, 43) or to be slightly higher in Fischer rats (11, 25, 42). Interestingly, the spread of individual values (between 0–100 ng/ml) reported in one study (16), suggests that animals were being sampled at different points of a basal pulse. Together, such observations suggest that single point determinations of dynamic HPA activity may not be able to discriminate fully between the two strains and could be misleading.
In the Lewis rat, it could be clearly seen that the circadian pattern of basal corticosterone release was largely due to a circadian variation in pulse height, which was greater in the evening than in the early morning. Such circadian differences in pulse height have also been seen to contribute to the daily variation in overall circulating hormone levels in other strains of rat (9) and in humans (1, 3, 4). In contrast, our studies show that female Fischer rats have higher mean circulating corticosterone concentrations and lack circadian variation. Comparison with the Lewis rat suggested that this was due to an elevation in the height of the morning pulses to levels similar to those seen in the evening. Most previous reports comparing circadian variations in circulating corticosterone concentrations between these two strains have compared male animals (19, 40, 41, 43, 44). In contrast to the female animals, male Lewis rats show a blunted circadian rhythm compared with male Fischer rats, which is due to a loss of the evening peak of corticosterone release (19, 40, 41, 44). However, one direct comparison of male and female Lewis rats has shown a robust circadian rhythm in the female, similar to that seen in the present studies, but a characteristically blunted rhythm in the male (41). These studies provide clear evidence for sexual dimorphism in HPA activity.
The maintenance of nocturnal pulse height through the morning and the resulting lack of circadian rhythmicity in the female Fischer rat suggest an insensitivity to the corticosterone feedback mechanisms thought to modulate circadian activity. Such a strain difference in glucocorticoid negative feedback is supported by the observation that ACTH levels rise to a greater extent in female Lewis rats than in Fischer rats after adrenalectomy (43). It has been suggested that this feedback is mediated via glucocorticoid action on high affinity type I, or mineralocorticoid receptors, within the hippocampus (45). However, differences in mineralocorticoid receptor messenger RNA expression, receptor numbers, receptor affinity, or receptor activation have not been detected between the two strains (19, 22, 46), suggesting that any difference must lie in the transduction of negative feedback signals. Other mechanisms mediating circadian rhythmicity also need to be investigated. In this respect it is interesting that splanchnic nerve transection in male Sprague-Dawley rats increases corticosterone pulses only during the light phase of the circadian cycle (7), similar to that in Fischer rats. It is possible, therefore, that differences in sympathetic regulation of adrenal sensitivity may represent one mechanism that could contribute to variations in the dynamics of HPA function.
Strain differences in stress responsiveness
White noise stress has been well characterized as a mild
psychological stress in the rat (9, 28, 47), and although both Lewis and
Fischer rats responded to this stress, clear strain differences were
apparent. As expected the integrated HPA response was greater in the
Fischer than in the Lewis rat. This is consistent with the reported
strain differences seen in response to a wide range of stresses (16, 18, 19, 20, 21, 22, 23, 24). Dynamic sampling has now allowed a more detailed examination
of the characteristics of these responses and showed a fundamental
difference in the relationship between basal and stimulated HPA
activity between the two strains. In the female Lewis rat, HPA activity
was characterized by periods when the animals were unable to respond to
the noise stress. As these periods coincided with the falling phase of
each basal pulse, they probably represent periods of inhibition of the
HPA axis. Such a relationship appears to be a characteristic of HPA
function in the rat and has been demonstrated in two other strains
[Sprague-Dawley (8) and Piebald-Viral-Glaxo (48)]. However, a most
striking result from these present studies is the observation that the
Fischer rat, which is known to be hyperresponsive to stress (18, 19, 20, 21, 22, 23, 24),
showed a complete absence of this relationship. These animals responded
equally to a stress regardless of when it occurred in relation to the
phase of the endogenous corticosterone pulse, and this resulted in
animals with a marked increase in their overall responsiveness to noise
stress.
The mechanisms responsible for terminating the pulse of basal HPA secretion in the Lewis rat, leading both to the dramatic fall in circulating hormone concentrations during the interpulse period and to the associated periods of stress hyporesponsiveness, are of considerable interest, especially as changes in this regulatory system might underlie the differential responsiveness of the two strains. It is possible that termination involves glucocorticoid negative feedback, as has been suggested for the circadian differences. If steroid feedback is involved, the rapid nature of the inhibition similar to that previously described after exogenous corticosterone administration (49), suggests a fast negative feedback mechanism. For the responses to be so rapid, a nongenomic action of the steroid may play a role, and a number of potential mechanisms have recently been exposed (50). Apart from steroid feedback, other inhibitory mechanisms that are known to differ between the two strains may play an important role. For example, the GABA-benzodiazepine receptor is known to mediate many of the central inhibitory influences on the HPA axis, and Fischer rats have a lower number of hypothalamic benzodiazepine receptors than Lewis rats (42). The relationship between altered central inhibitory pathways and the transcription, translation, and secretion of CRF is unclear. The Lewis rats do have a markedly smaller CRF response to stress than the Fisher rats (12, 13, 16), suggesting a decreased responsiveness of the CRF neurons to afferent stressful stimuli. In keeping with a hypothalamic or suprahypothalamic site being responsible for the postpulse refractoriness, we have shown that the response to exogenous CRH is unaffected by the timing of the injection relative to the rising or falling phase of the endogenous pulse mechanism. This effectively excludes both the anterior pituitary and the adrenal cortex as the site responsible for the postpulse hyporesponsiveness to stress. This must, therefore, be occurring at the suprapituitary level and may result in decreased activation of hypothalamic CRH neurons and thus decreased CRH and perhaps vasopressin release. Differences in the response characteristics at this same suprapituitary site are also likely to be responsible for the different characteristics of the stress response in Fisher and Lewis rats. These differences in CRF release may also be compounded by differences in pituitary sensitivity, as suggested by the fact that CRF infusions into the two strains induce a more rapid response in Fisher rats. This is supported by observations that administration of CRF at a lower dose of 0.5 µg has been shown to release significantly less ACTH in female Lewis than in female Fisher rats (26).
Pronounced strain differences in the duration of stress-induced corticosterone release were also seen in the studies reported here. The response in the Lewis rat was fairly transient, as has been seen in other rat strains (9, 28, 47), whereas Fischer rats showed a prolonged stress response. Similar differences have been previously observed (24) and suggest a possible deficit in negative feedback in the Fischer rat, which might implicate the type II or glucocorticoid receptor (GR). Although GR messenger RNA within the hippocampus does appear to be lower in Fischer female compared with Lewis rats (46), no strain differences in GR receptor binding have been reported (19, 40). Thus, although negative feedback may play a major role in the strain differences in basal and stimulated HPA function between Lewis and Fischer rats, the major differences are not likely to occur at the level of receptor numbers, but, rather, in the transduction of the signal to the HPA axis.
Strain-dependent behavioral responses to stress
Strain differences were also evident in the behavioral responses
of the animals to the noise stress. Fischer rats showed much greater
increases in all parameters, particularly during the period of the
noise stress. Interestingly, both grooming and rearing activities are
believed to be mediated by a central action of the peptide CRF and are
induced by central administration of the peptide (51). Therefore, the
differences in behavior may be related to the relative stress-induced
expression of CRF in Lewis animals (12, 13, 16). Similar strain
differences in grooming (16, 52) and rearing (21) in animals placed in
novel environments have previously been seen. Both grooming and rearing
are stereotypical anxiety-related behaviors, suggesting that Lewis rats
are less anxious during the stress period than Fischer rats. A similar
conclusion has been drawn from the behavior of the two strains in the
open field arena and on the elevated plus maze (16, 53, 21). Therefore,
our studies, in which we were able to study the animals in their home
environment with no operator interaction, confirm the conclusions of
these earlier studies and suggest that female Fischer rats are indeed
more reactive to stress.
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Acknowledgments |
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Footnotes |
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Received March 9, 1998.
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