Circadian Rhythm Of Plasma Corticosterone Research Articles

Postnatal Ontogeny of the Circadian Expression of the Adrenal Clock Genes and Corticosterone Rhythm in Male Rats.

The postnatal synchronization of the circadian variation of the adrenal clock genes in mammals remains unknown. We evaluated the postnatal ontogeny of daily variation of clock genes (Clock/Bmal1/Per1/Per2/Per3/Cry1/Cry2/Rorα/Rev-Erbα) and steroidogenesis-related genes (Star and Mc2r) in rat adrenals and its relationship with the emergence of plasma corticosterone rhythm using cosinor analysis. Plasma corticosterone circadian rhythm was detected from postnatal day (P)1, with morning acrophase, between zeitgeber time (ZT)0 and ZT2. From P14, there was a nocturnal acrophase of corticosterone at ZT20, which was associated with pups' eye opening. From P3 there was a circadian variation of the mRNA expression of Bmal1, Per2, Per3, and Cry1 genes with morning acrophase, whereas Rev-Erbα had nocturnal acrophase. From P14, Bmal1, Per2, Per3, and Cry1 acrophases advanced by approximately 10 hours, as compared with early neonatal days, becoming vespertine-nocturnal. In all postnatal ages, Per2 and Cry1 circadian profiles were synchronized in phase with the circadian rhythm of plasma corticosterone, whereas Bmal1 was in antiphase. An adult-like Star circadian rhythm profile was observed only from P21. In conclusion, our original data demonstrated a progressive postnatal maturation of the circadian variation of the adrenal clock genes in synchrony with the development of the corticosterone circadian rhythm in rats.

Depression‐like behavior in the forced swimming test in PACAP‐deficient mice: amelioration by the atypical antipsychotic risperidone

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with pleiotropic functions. We report here that PACAP-deficient (PACAP-/-) mice showed increased immobility in a forced swimming test, which was reduced by the antidepressant desipramine, to a similar extent as in wild-type mice. The atypical antipsychotic risperidone and the selective serotonin (5-HT)(2) antagonist ritanserin normalized the depression-like behavior in PACAP-/- mice. The 5-HT(2) agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine-induced 5-HT syndrome was exaggerated in PACAP-/- mice, which suggests a 5-HT(2)-receptor-dependent mechanism in the depression-like behavior. The circadian rhythm of plasma corticosterone and body core temperature was significantly flattened in the mutants. mRNA expression of glucocorticoid receptor was reduced in the mutant hippocampus. The present results suggest that alterations in PACAP signaling might contribute to the pathogenesis of certain depressive conditions amenable to atypical antipsychotic drugs.

Modeling Circadian Rhythms of Glucocorticoid Receptor and Glutamine Synthetase Expression in Rat Skeletal Muscle

The circadian rhythm of endogenous corticosterone (CS) may produce fluctuations of downstream gene expression in normal rats. This study examined changes in glucocorticoid receptor (GR) and glutamine synthetase (GS) expression in rat skeletal muscle in relation to plasma CS over a 24-h period. Fifty-four normal male Wistar rats were sacrificed at 18 time points (n = 3) over 24 h. Plasma CS concentrations and gastrocnemius muscle GR and GS mRNA and GS activity were measured. The circadian rhythm of plasma CS was captured by a two-harmonic function. The expression of GR and GS mRNA and GS activity follow a circadian rhythm in normal rat skeletal muscle. GR mRNA reaches a trough at 4 h after the peak of plasma CS and it fluctuates between 0.55 and 0.9 fmol g tissue(-1). GS mRNA and activity reach peaks at 6 and 12 h after the endogenous CS peak. GS mRNA oscillates between 3 and 6 fmol g tissue(-1), whereas GS activity fluctuates between 17 and 23 micromol min(-1) g protein(-1). Mechanistic receptor/gene-mediated pharmacodynamic models were applied to describe the temporal patterns of GR mRNA, GS mRNA, and GS activity within the circadian cycle. The integrated models were able to capture the circadian expression patterns of plasma CS, and GR and GS in normal rat skeletal muscle showing a dependence of tissue gene expression on plasma CS.

Diurnal variation in rat liver thyroid hormone receptor (TR)-alpha messenger ribonucleic acid (mRNA) is dependent on the biological clock in the suprachiasmatic nucleus, whereas diurnal variation of TR beta 1 mRNA is modified by food intake.

Previous studies have shown a diurnal variation of certain isoforms of thyroid hormone receptors (TR) in rat liver. The genesis of these diurnal changes is still unknown. To clarify whether the biological clock, located in the hypothalamic suprachiasmatic nucleus (SCN), is involved, we made selective SCN lesions. Rats with an SCN lesion lost their circadian rhythm of plasma corticosterone and TSH when compared with intact animals. TR alpha 1 and TR alpha 2 mRNA expression of control rats was higher in the light period than in the dark period; changes that were abolished in the rats with SCN lesions. In contrast, liver TR beta 1 mRNA of intact rats showed a diurnal variation that failed to reach statistical significance. To evaluate whether these effects could be explained indirectly by the disappearance of rhythmic feeding behavior in rats with SCN lesions, we performed a second experiment in which otherwise intact animals were subjected to a regular feeding (RF) schedule, with one meal every 4 h. When compared with rats with free access to food, RF only affected TR beta 1 mRNA expression and had no effect on the diurnal changes in TR alpha 1 and TR alpha 2. We conclude that liver TR beta 1 expression is most clearly affected by food intake. Diurnal changes in liver TR alpha 1 and TR alpha 2 are controlled by the biological clock in the SCN but not via changes in the daily rhythm of food intake. The findings may have physiological relevance for diurnal variation of T(3)-dependent gene expression, which is supported by a diurnal variation in the expression of the 5'-deiodinase gene.

Daily Changes of Plasma Corticosterone by an 8-h Daytime Feeding Occur Without Body Weight Loss or Severe Food Restriction in the Rat

Different studies have reported that daytime feeding entrains the circadian rhythm of corticosterone secretion in rats. However, it remained unclear whether calorie restriction or daytime feeding access have an effect. The aim of our study is to evaluate the effect of an 8-h daytime feeding access on the circadian rhythm of plasma corticosterone. Eleven adult male Wistar rats were assigned to two different conditions of access to food: ad lib feeding for one week and daytime feeding for the following two weeks. On the 7th, 14th and 21st day, blood samples were collected every 4 h from 08:00 to 04:00. Food intake and body weight were recorded daily. During daytime feeding, rats ingested 88% of the amount of food ingested over 24 h in the ad lib feeding period. However, body weight increased significantly from the first day to the end of experiment. Peak plasma corticosterone was 12 h shifted during daytime feeding period compared to the ad lib condition. This study showed that an 8-h daytime feeding entrained the circadian rhythm of plasma corticosterone without body weight loss or severe food restriction.

Alteration in circadian rhythm of plasma corticosterone in rats following sociopsychological stress induced by communication box

The purpose of present study was to investigate the physiological characteristics of sociopsychological stress induced by the communication box method. In this method, the nonfoot shocked rats were used as the psychological stressed experimental group. The stress exposure was loaded for 1 h between 0900 and 1000, daily. The changes in circadian rhythm of plasma corticosterone were studied following the 3-day, 5-day, or 10-day stress exposure, respectively. Plasma corticosterone levels of foot shocked rats and nonfoot shocked rats following the 3-day or 5-day stress exposure were significantly higher than those of control rats. Particularly, the marked elevation of plasma corticosterone was observed at the peak time of circadian rhythm (2100) in the both stress groups. Consequently, the amplitude of 24 h rhythm increased significantly, but the acrophase was not changed. However, the changes of plasma corticosterone levels of both stress groups following the 10-day stress exposure approached those of control group. These results suggest that the repeated exposure of sociopsychological stress can influence the circadian rhythm of plasma corticosterone. The communication box method may be a valuable tool for researching the etiology of human psychiatric disorders with rhythm disturbance.

Analysis of corticosterone in rat plasma by high-performance liquid chromatography

A sensitive and specific high-performance liquid chromatographic assay for the determination of corticosterone in rat plasma using dexamethasone as the internal standard is reported. Rat plasma (0.5 ml) is extracted with methylene chloride, washed with 0.1 M sodium hydroxide and then with water. The extract is analyzed by HPLC on a C 18 column with ultraviolet absorbance detection at 254 nm. Pooled rat plasma was treated with activated decolorizing carbon to remove endogenous corticosterone, and was then used to prepare standards for the assay. Using 0.5 ml plasma for extraction, the detection limit of the assay is 10 ng/ml. The standard curve is linear over the concentration range 10–500 ng/ml. The recovery of corticosterone after extraction was independent of concentration and ranged from 87 to 95%. The coefficient of variation for intra-day and inter-day precision ranged from 2.4 to 7.4% and 2.1 to 8.7%, respectively. In addition, for concentrations ranging from 10 to 500 ng/ml the accuracy is within 5% of the spiked standards. The assay was utilized to examine the circadian rhythm of plasma corticosterone, and to examine the effect of immobilization stress on corticosterone levels in rats.

Circadian rhythms of plasma corticosterone at different times after induction of diabetes. Responses to corticoadrenal stimulation in light and dark phases

In this study we have tried to determine the effects of streptozotocin-induced (50 mg/kg) diabetes (15 and 30 day duration) on circadian rhythms of plasma corticosterone concentrations and on the responsiveness of the adrenal glands to exogenously administered ACTH at the time of maximum and minimum levels of plasma corticosterone. Rats were kept under controlled lighting 12h light/12h dark (12L/12D) and fed ad libitum. The corticosteroid circadian pattern in control (C) rats is characterized as one in which peak corticosterone concentrations occur at the beginning of the dark phase (activity period), with a decrease over the remainder of the 24h period. Circadian rhythmicity of plasma corticosterone concentration was absent in the diabetic rats 15 days after induction (D15 rats), with higher mean levels than the C. However, in the diabetic rats 30 days after induction (D30 rats) there is a recovery of this rhythm with similar acrophase and amplitude to the C rats. One hour after stimulation by ACTH (5 IU/kg) at the time of maximum and minimum levels of plasma corticosterone, the C rats showed similar plasma corticosterone levels. In the D15 rats, levels of corticosterone in the light phase one hour after ACTH administration were higher than in the dark phase; being lower than C in this phase. The loss of capacity to respond during the dark phase may be due to adrenal blunting in this phase with high levels of plasma corticosterone. In D30 rats, there is a more noticeable loss of capacity for adrenal response in the light than in the dark phase, with values lower than C and D15 rats in both phases. These findings suggest that the duration of diabetes has a significant role in both plasma corticosterone rhythms and adrenal sensitivity to ACTH administration.

Sex and strain differences in the circadian rhythm fluctuation of endocrine and immune function in the rat: implications for rodent models of autoimmune disease

This study compares 24-h basal patterns of corticosterone and immunoreactivity for Lewis and Fischer (F344) strain rats. Significant differences in the circadian rhythm of plasma corticosterone were found across sex and strain. Male Lewis rats exhibited significantly lower 24-h corticosterone levels relative to female Lewis and male F344 rats. In addition, male Lewis rats were found to have higher mononuclear cell counts than female Lewis or male F344 rats, particularly in the peripheral blood and spleen compartments. Levels of CD4-bearing lymphocytes in blood, lymph node, and spleen were found to be higher in Lewis rats compared to the F344 strain over a 24-h period. In general, percentages of CD8- and major histocompatibility complex (MHC) class II-bearing lymphocytes were shown to vary over 24 h in all compartments across strains. Given that the Lewis rat has low basal levels of circulating corticosterone, and comparatively higher numbers of CD4-bearing lymphocytes, these factors may play a causative role in the known susceptibility of this strain to many experimental models of autoimmune disease.

The metabolic clearance rate of corticosterone in lean and obese male Zucker rats

The obese Zucker rat is an animal model of human juvenile-onset obesity. There rats exhibit numerous endocrine and metabolic abnormalities. Adrenalectomy of obese rats has been shown to reduce or reverse several of these abnormalities, thereby implying that corticosterone may contribute to the expression of obesity in this animal. Furthermore, it has been shown that the circadian rhythm of plasma corticosterone is disturbed in obese Zucker rats resulting in elevated morning plasma corticosterone concentrations in obese rats as compared to lean rats. In a effort to better elucidate the mechanism of the elevated morning levels of plasma corticosterone, the metabolic clearance rate of corticosterone was determined in the morning for lean and obese male Zucker rats (12 to 20 weeks). Additionally, the biliary and urinary excretion of labeled corticosterone and/or its metabolites were determined. The metabolic clearance rate of corticosterone was significantly greater in obese rats than in their lean counterparts. Both the metabolic clearance rate and the volume of compartments significantly correlated with body weight. No correlation was found between body weight and the elimination rate constant. The increased metabolic clearance rate of obese rats appeared to be due to an increase in the physiologic distribution of corticosterone and not to an alteration in the enzymes responsible for corticosterone metabolism. It appears that the metabolic clearance rate of corticosterone in obese Zucker rats does not contribute to elevated morning concentrations of plasma corticosterone previously observed in these animals. It suggests that the adrenal corticosterone secretion rate must actually be greater than one would expect from the plasma corticosterone concentrations alone.

Effects of Pantothenate Deficiency on Steroid Hormone Secretion in Rats

The effect of pantothenic acid (PA) deficiency on the adrenocortical function was investigated in young male rats fed a PA-deficient (PAD) diet over a period of about three months. Pair-weight (PW) and ad libitum (AL) fed rats served as controls. Basal 08.00h (lights on) plasma levels of corticosterone were regularly found to be reduced in PAD and AL rats compared with those in PW animals. Investigation of the circadian rhythm of plasma corticosterone revealed that the elevated 08.00h hormone concentrations of PW rats are due to a biphasic 24-h pattern of plasma corticosterone with a distinct glucocorticoid peak at lights on and another one at lights off (20.00h), whereas PAD and AL rats only show one clear increase in plasma corticosterone levels at the beginning of the dark period. However, the evening glucocorticoid peak of the PAD rats was markedly higher than that of the PW and AL groups. Thus an adrenocortical overactivity is ascertained in PA deficiency which is presumably responsible for the adrenal hypertrophy generally observed in earlier studies on PA depletion in rats. Multiple examinations of the secretory capacity for corticosterone, each carried out half an hour after i.m. administration of 2.5 IU ACTH1-24, revealed comparable plasma responses to supraphysiological ACTH stimulation in PAD, PW, and AL rats. Therefore we concluded that corticosterone secretion is not impaired in PA deficiency, at least not that elicited for short periods by adrenocortical overstimulation. Additional measurements of the adrenal cholesterol content and the circadian plasma levels of dehydroepiandrosterone-sulphate were carried out in all three diet groups. The respective results are discussed with regard to the stress situation produced by the experimental PA deficiency.

Effects of Pantothenate Deficiency on Steroid Hormone Secretion in Rats

The effect of pantothenic acid (PA) deficiency on the adrenocortical function was investigated in young male rats fed a PA-deficient (PAD) diet over a period of about three months. Pair-weight (PW) and ad libitum (AL) fed rats served as controls. Basal 08.00h (lights on) plasma levels of corticosterone were regularly found to be reduced in PAD and AL rats compared with those in PW animals. Investigation of the circadian rhythm of plasma corticosterone revealed that the elevated 08.00h hormone concentrations of PW rats are due to a biphasic 24-h pattern of plasma corticosterone with a distinct glucocorticoid peak at lights on and another one at lights off (20.00h), whereas PAD and AL rats only show one clear increase in plasma corticosterone levels at the beginning of the dark period. However, the evening glucocorticoid peak of the PAD rats was markedly higher than that of the PW and AL groups. Thus an adrenocortical overactivity is ascertained in PA deficiency which is presumably responsible for the adrenal hypertrophy generally observed in earlier studies on PA depletion in rats. Multiple examinations of the secretory capacity for corticosterone, each carried out half an hour after i.m. administration of 2.5 IU ACTH1-24, revealed comparable plasma responses to supraphysiological ACTH stimulation in PAD, PW, and AL rats. Therefore we concluded that corticosterone secretion is not impaired in PA deficiency, at least not that elicited for short periods by adrenocortical overstimulation. Additional measurements of the adrenal cholesterol content and the circadian plasma levels of dehydroepiandrosterone-sulphate were carried out in all three diet groups. The respective results are discussed with regard to the stress situation produced by the experimental PA deficiency.

Circadian rhythm of corticosterone in diabetic rats

We proposed that the circadian rhythm of corticosterone in diabetic rats would have a different pattern than that in non-diabetic control rats. To test this hypothesis, 20 male Sprague-Dawley rats were given ad libitum access to a stock diet and housed individually in a light and temperature controlled room. Ten rats were made diabetic by two subcutaneous injections of streptozotocin. Ten rats which were not injected served as controls. Thirteen days after induction of the diabetes, tail blood samples were taken every 4 h for 24 h. Plasma corticosterone levels were significantly higher in diabetic rats than in control rats at 3 time points during the light cycle; however, concentrations were similar during the dark cycle. We speculate that diabetes may cause alterations in the steroid feedback mechanism to the hypothalamus and/or pituitary, resulting in an abnormal circadian rhythm of plasma corticosterone.

High-performance liquid chromatographic separation of corticosteroids in plasma of rats. Its application to the determination of the circadian rhythm of 18-hydroxycorticosterone related to aldosterone and corticosterone.

An efficient separation of corticosteroids in plasma of rats was obtained by reversed-phase high-performance liquid chromatography (HPLC). Plasma corticosteroid assays with HPLC separation were used to determine the circadian rhythm of 18-hydroxycorticosterone (18-OHB) and its possible relationship to aldosterone or corticosterone in conscious rats under standard conditions (regular diet; 12-hour light and 12-hour dark cycle). Significant circadian rhythms of plasma corticosterone, 18-OHB and aldosterone were observed with peak values at 20.00 h and nadir values at 08.00 h. The mean ratio of plasma 18-OHB to aldosterone during 24 h was 2.4. The circadian rhythm of 18-OHB was also correlated with that of plasma aldosterone or corticosterone.

Changes in the circadian rhythm of plasma corticosterone by histamine depletion in rats

Changes in the circadian rhythm of plasma corticosterone by histamine depletion in rats

Dissociation of circadian rhythms in rats with a hypothalamic island

Complete isolation of the medial basal hypothalamus, including the suprachiasmatic nuclei in the isolated island, from the rest of the central nervous system was performed in rats. The circadian rhythm of plasma corticosterone level remained essentially intact in 5 of 16 rats with complete islands, whereas that of spontaneous locomotor activity was decomposed into ultradian bursts in 15 rats, resulting in a clear dissociation of the two rhythms in four rats. One rat, whose circadian rhythm of both variables persisted after the hypothalamic isolation, showed a diurnal activity. The 24-h patterns of plasma corticosterone of the other rats could be characterized as either episodic or continuously low throughout the day. A prefeeding corticosterone peak was detected under restricted feeding in rats with episodic fluctuations but not in those with continuously low hormone levels. It is concluded that the hypothalamic island includes the fundamental structures necessary for the manifestation of the entrained circadian rhythm of plasma corticosterone in rats under ad libitum feeding, whereas it contains only a part of that for spontaneous locomotor activity. The coupling pathways from the circadian oscillator(s) to these overt rhythms seem to be separate in the central nervous system, and the circadian rhythm of plasma corticosterone is not a direct consequence of that of locomotor activity.

Maternal-fetal coordination in the synchronization of circadian rhythm of plasma corticosterone in rats

Maternal-fetal coordination in the synchronization of circadian rhythm of plasma corticosterone in rats

Ontogeny of an oscillation underlying the circadian rhythm of plasma corticosterone in rats

In previous reports ( J. Physiol. 325, 493, 507, 521, 1982) we have suggested a prenatal onset of the circadian oscillation in rats. This was based mainly on the findings obtained in pups which were reared by an alternating nursing. In the present study we have applied this technique to experiments which were designed to determine the stage of gestation in the original mother that decided the phase angle of pup's hormone rhythm which was to develop later in the postnatal life. In this experiment we observed, though preliminarily, that reversal of the light-dark cycle of the pregnant mother at day 10 of pregnancy resulted in an effective reversal of pup's hormone rhythm, whereas the reversal at day 17 of pregnancy failed to affect it. From these results it is surmised that the original mother primarily determined the phase angle of the circadian oscillation in the fetus prior to the 17th day of gestation.

Prenatal onset and maternal modifications of the circadian rhythm of plasma corticosterone in blind infantile rats.

1. In order to clarify the manner in which maternal nursing modifies the circadian rhythm of plasma corticosterone in blind pups, specified schedules of maternal nursing were imposed on blind pups and the hormone rhythm was followed individually. 2. Two groups of blinded pups were continuously nursed, alternately by two mother rats having different circadian phases of lactating period. In both groups, phase angles of the original mother were predominantly reflected in the phase of the pups' hormone rhythm. 3. When the maternal nursing was limited only during the light period (L nursing), it caused no detectable effect on the pups' hormone rhythm. 4. In contrast, when the maternal nursing was limited only during the dark period (D nursing), approximately one half of the pups at the fourth post-natal week showed a bimodal pattern of hormone rhythm. A second peak appearing 180 degrees out of phase to the first peak disappeared by the sixth or eight post-natal week. 5. It is concluded that the circadian oscillation underlying the plasma corticosterone rhythm starts to function prenatally and the original mother (probably, a prenatal LD cycle) primarily determines the phase angle of the circadian oscillation in blind pups. The maternal nursing does not entrain the pups' circadian oscillation, but does modify transiently the overt hormone rhythm, probably through a discord between maternal nursing and pups' feeding phases.

Ontogeny of the circadian rhythm of plasma corticosterone in blind infantile rats.

1. Post-natal manifestation of plasma corticosterone rhythm was followed by individual pups until the end of 12 weeks of life. Results obtained were analysed by both visual inspection and a least squares spectrum method. The validity of the approaches used was evaluated. 2. Circadian rhythm of plasma corticosterone in sighted pups under light-dark cycle (LD) first appeared at around the third post-natal week, accompanied often with a bimodal pattern: a second peak being counterphased to the first main peak. The second peak became obscure at the fourth week, disappearing as pups matured. 3. The hormone rhythm in blinded pups whose eyes were removed within 16 h of birth was free-running under LD with a period of 24.40 +/- 0.02 h (mean +/- S.E.M.). The free-running period was stable until at least the end of the twelfth week of life. 4. The acrophase of the circadian rhythm in blind pups born and reared under LD was 180 degrees out of phase to that born and reared under DL, a reversed light-dark condition. In each case, the acrophase shifted about 8 h from that of sighted pups at the fourth week of life. 5. It is suggested that an underlying oscillator for the hormone rhythm starts to oscillate earlier than the fourth week of life and the environmental light-dark cycle prior to the fourth week determines the phase angle of the circadian rhythm in blind pups.