Circadian Corticosterone Rhythm Research Articles

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.

CNS control of the circadian adrenocortical rhythm

The effects of various CNS impairments on the circadian rhythm of plasma ACTH and Corticosterone (C) were studied in individual cannulated female Sprague-Dawley rats. Pinealectomy had no effect whatever the light perception (intact or blinded rats). Bilateral ablation of paraventricular nuclei did not obliterate the hormonal rhythms, although the rhythms' amplitude were markedly depressed. On the other hand, destruction of suprachiasmatic nuclei (SCN) or systemic blockade of the serotoninergic (5-HT) system by pCPA blocked ACTH rhythm at baseline levels, although circadian or ultradian fluctuations with normal amplitudes persisted for C. Similar effect was observed in several blinded rats with raphe lesions suppressing 5-HT innervation of SCN. Daily 5-HTP injections, if given 4 h after dawn restored normal ACTH rhythm. The respective role of related structures in the rhythms' control will be discussed.

Ontogeny of circadian corticosterone rhythm in rats treated with monosodium glutamate neonatally

A lesion of the arcuate nucleus (ARC) was produced by subcutaneous administration of monosodium glutamate (MSG) to neonatal female rats. The onset and the amplitude of the circadian corticosterone rhythm in the MSG-treated rats were the same as those in the saline-injected controls. When rats were blinded at 35 days of age, the corticosterone rhythm free-runned in both groups. The results indicate that the neurons in the ARC do not play an essential role in the mediation circadian signals from the suprachiasmatic nucleus to the pituitary-adrenocortical system. MSG-treatment, however, seems to delay the phase shift of free-running corticosterone rhythm through yet unknown mechanisms.

Rate-limiting, diurnal activity of hepatic microsomal cholesterol-7α-hydroxylase in pigeons with high serum cholesterol

Efficiency of regulating serum cholesterol by Cholesterol-7α-hydroxylase was studied in pigeon strains hypo-(SR-39) and hypercholesterolemic (SR-37) with respect to dietary cholesterol. Diurnal hydroxylase activity in SR-37 was 10% of that in strain SR-39 adapted to a light-dark cycle and fed a non-cholesterol diet. Acrophase (6 p.m.) activity was 54-fold greater in SR-39 than in SR-37 pigeons. Dietary cholesterol elevated enzyme activity 2.8-fold in SR-37 pigeons. Dietary cholestyramine plus cholesterol increased hydroxylase activity 21-fold in SR-37 and 3-fold in SR-39 strain; yet, activity remained greater in SR-39. Cholestyramine feeding prevented elevated cholesterol levels in both groups. The circadian rhythms of hydroxylase and serum corticosterone were determined. The diurnal activity in SR-37 was 10% of that in SR-39 and acrophase activity was 34-fold greater in SR-39. Hormone levels were comparable. Programmed acrophase was asynchronous between strains. Hydroxylase activity was positively correlated with corticosterone levels and inversely correlated with serum cholesterol. A defect in the up-regulation of Cholesterol-7α-hydroxylase is proposed which limits the catabolism of cholesterol in strain SR-37.

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.

Possible zeitgebers for external entrainment of the circadian rhythm of plasma corticosterone in blind infantile rats.

1. The phase angle of circadian rhythm of plasma corticosterone in individual blind pups was followed in order to find out an effective zeitgeber(s) during the post-natal development. 2. The retinal light pathway before the opening of eyes was not essential for the entrainment of pups' rhythm to the environmental light-dark (LD) cycle. 3. In blinded pups whose eyes were enucleated on the day of birth, no evidence was obtained for effective extra-retinal pathways for photic inputs. 4. Free-running circadian hormone rhythm of blind pups was not entrained by 'social contact' with other sighted pups in the same cage. 5. Even when the duration of nursing was varied from 2 to 4 weeks, the phase angle of pups' rhythm at the fourth week was not affected. 6. In mother-pups exchange experiments in which pups born from LD mother were reared by DL mother (LD-DL pups) and conversely, pups from DL original mother were reared by LD foster mother (DL-LD pups), about one half of the pups at the fourth post-natal week of both groups exhibited phase angles belonging to their original mothers and the other half showed phase angles of their foster mothers. 7. It is suggested that blind pups may retain the phase angle of circadian rhythm of the original mother and the overt hormone rhythm may be modifiable by the foster mother during the early phase of post-natal life.

Adrenocorticotropic regulations after bilateral lesions of the paraventricular or supraoptic nuclei and in Brattleboro rats.

The circadian rhythm and ether stress responsiveness of plasma ACTH and corticosterone were explored in chronically cannulated female Sprague-Dawley rats with bilateral lesions of either the paraventricular nuclei (PVN) or supraoptic nuclei and also in female Brattleboro rats. 3 weeks after PVN lesions, the circadian ACTH rhythm had dropped by at least half. Less drastic alterations were measured for the corticosterone rhythm, and only its diurnal maximum and amplitude diminished by one third. Although the kinetics of plasma ACTH and corticosterone stimulation after ether stress were essentially normal, the peaks for both hormones, 5–15 min after stress, were only half as high as the control peaks. The effects of bilateral abolition of supraoptic nuclei on the circadian rhythm of the adrenocorticotropic system were slight, and only the diurnal minimum and mean level of ACTH dropped significantly. Intriguingly, both ACTH and corticosterone levels in rats with supraoptic lesions rose to twice the control levels after ether stress. In Brattleboro rats, neither the circadian rhythm nor stress-induced stimulation of ACTH and corticosterone differed from those of the controls. These data indicate that vasopressin is not essential for either of the regulations of the adrenocorticotropic system. The production of corticotropin-releasing factor (CRF) involved in both types of regulation clearly originates, at least partly, from the PVN area and no significant contribution is made by the region of the supraoptic nuclei, a finding which conforms to neuroanatomical data. However, it is not yet clear whether the PVN area is the site of origin of the recently characterized 41 amino-acid CRF or of other CRF fractions distinct from vasopressin.

Effects of maternal ethanol consumption in rats on basal and rhythmic pituitary - adrenal function in neonatal offspring

Neonatal corticoid treatment delays development of the circadian rhythm of plasma corticosterone in rats. We therefore sought to determine whether fetal or neonatal exposure to ethanol, a substance which activates the hypothalamo - pituitary - adrenal axis, produces similar effects. Subjects were the offspring of dams fed a 5.0% w/v ethanol-containing liquid diet or pair-fed an isocaloric control diet during gestation weeks two and three or during postnatal week one. At birth (day 1), the fetal ethanol-exposed pups had significantly higher brain and plasma corticosterone levels than the pair-fed or normal controls; brain and body weights were unaffected. By day 3, brain and plasma corticosterone titers in the fetal ethanol-exposed pups declined to the levels of the pair-fed and normal controls, although brain weights were significantly reduced. Significantly higher p.m. than a.m. levels of plasma corticosterone first occurred on day 18 both in the fetal ethanol-exposed pups and in the pair-fed and normal controls. Thus, despite its causing elevated corticosterone levels at birth, fetal exposure to ethanol did not affect the onset of the pituitary - adrenal circadian rhythm. On the other hand, exposure to ethanol during the first neonatal week delayed the onset of the pituitary - adrenal rhythm from day 18 to day 21. However, even greater delays occurred in the neonatal pair-fed controls, suggesting that the delays following neonatal exposure were due to nutritional deficits rather than to alcohol per se. The developmental and long-term influences of elevated corticoid levels at birth in fetal ethanol-exposed rats on other aspects of pituitary - adrenal function remain to be determined.

Circadian Adrenocortical Rhythm in the Adrenalectomized Rat With or Without Autotransplanted Adrenal Gland

Circadian rhythm of blood corticosterone in adrenalectomized rats with (AT rat) or without adrenal autotransplants was investigated. Blood samples were obtained individually at 4-hour intervals for a 24-hour period per week for 5-7 consecutive weeks by the tail tip incision method. Corticosterone responses of the autotransplanted adrenal gland to ACTH gradually increased with time after the implantation, and by 5 weeks had attained a level comparable to that of intact rats. Concurrently with this change, circadian adrenocortical rhythms in AT rats became evident and they were able to respond to reversed photoperiodic environment. The effects of constant illumination or food restriction on the corticosterone rhythm in AT rats were indistinguishable from those in intact rats in every respect. A sharp drop and disappearance of circadian periodicity were observed in the blood corticosterone levels by removal of autotransplanted adrenals. In some of the adrenalectomized rats, the daily rhythm of the blood corticosterone levels reappeared 5-7 weeks after surgery owing to the hypertrophy of accessory adrenal glands or regeneration from capsular fragment left in situ. These results suggest that neural input to the adrenal is not essential for the occurrence of circadian adrenocortical rhythms.

Effects of experimental diabetes on the concentration of corticosterone in central nervous system, serum and adrenal glands

Experiments were conducted in male rats to study effects of streptozotocin diabetes on (a) circadian rhythms of corticosterone in hypothalamus (HT), hippocampus (HC), cerebral cortex, serum and adrenals; (b) subcellular distribution of corticosterone in HT and HC, and (c) feeding patterns. Animals were kept under controlled lighting (07–1900 h) and killed at 4 h intervals. A daily rhythm of corticosterone concentration was found in brain regions, serum and adrenals of control animals with peak levels at 2100h and minima at 1300h. In diabetics a loss of the normal circadian variation was observed, with midday increments of corticosterone concentration in serum and tissues with respect to controls. The subcellular distribution of brain corticosterone was different in diabetics, with the majority of the steroid being present in cytosol of HT and HC. Consequently the nuclear-cytosol ratio for corticosterone was markedly reduced in HT and HC of diabetic animals. The feeding pattern of diabetic rats was also changed: whereas control animals consumed most of their food and water during the dark period, intake of diabetic rats was significantly greater during the light and lower than normal during the Clark period. These results indicate a disturbance in corticosterone variation of diabetic animals, and in view that feeding schedules may synchronize adrenocortical activity, the possibility exists that the altered feeding pattern was responsible for the abnormal rhythm. The change in the nuclear to cytosol distribution of corticosterone in diabetics suggests an impairment of the biological activity of the cortieoid in brain.

Effects of housing on corticosterone rhythm and stress responses in female mice

In a longitudinal study of grouping of virgin female mice, basal plasma corticosterone levels were significantly higher at 1 hour, 5 hours and 9 hours before lights off when the animals were grouped than when individually housed. There were no differences 3 hours, 7 hours and 11 hours after lights off. A week of daily vaginal smearing at the expected circadian peak elevated plasma corticosterone at that time of day but not at other times. A circadian rhythm of basal plasma corticosterone with highest values 1 hour before lights out was demonstrated, but there were no apparent differences in the rhythm phase in differentially housed mice. Group housed females, blood sampled and ether stressed, but not mice only ether stressed, had significantly higher plasma corticosterone levels than individually housed mice. There was no circadian rhythm in stress levels.

Circadian rhythm of plasma corticosterone in vagotomized rats.

In vagotomized rats, 2 weeks after surgery, the amplitude of the circadian rhythm of plasma corticosterone was extremely low, indicating that gastrointestinal activity may be in part involved in the hypothalamo-hypophyseal circadian rhythmicity.

Circadian corticosterone rhythm and stress response in rats with adrenal autotransplants.

A significant circadian variation in plasma corticosterone concentrations as determined by sequential sampling was observed in rats with adrenals autotransplanted (ADT) to the inguinal region as well as in sham-operated controls when studied 3 wk after surgery. Phase shifting of plasma corticosterone concentrations was observed in a second ADT group placed in reverse photoperiod (D12:L12, lights on 1900) for 2 wk. Intravenous injections of ACTH in dexamethasone-suppressed animals resulted in significant increments in plasma corticosterone concentrations in sham-operated but not in ADT animals. ADT and sham groups both showed elevated plasma corticosterone concentrations after ether or 30-min immobilization stress, although greater responses were present in the sham group. It appears that direct innervation of the adrenal is unnecessary for the maintenance of circadian plasma corticosterone concentrations or certain stress responses.

Neonatal dexamethasone administration. I. Temporary delay of development of the circadian serum corticosterone rhythm in rats.

A series of experiments was undertaken to examine the effects of neonatal dexamethasone administration on the development of the circadian serum corticosterone rhythm in rats. Initial experiments showed that the rhythm began normally on postnatal day 18 in untreated animals. Then 1-day-old rats were injected sc with dexamethasone acetate (1, 10, or 100 microgram), dexamethasone phosphate (1, 3, or 5 microgram) beginning on day 1. Appropriate vehicle controls were included. At most doses and dosage regimens, rat pups were sacrificed at 0700 and 1900 h on postnatal days 16, 18, 20, and 22, but at the highest doses, they were sacrificed only on days 25 and 30. The single dexamethasone acetate injection (100 microgram) delayed the appearance of the corticosterone rhythm for 2 days compared to that in the vehicle-injected controls. Similarly, the 3 consecutive injections of dexamethasone phosphate (5 microgram) delayed the appearance of the rhythm for 4 days. All other dexamethasone dosage regimens were ineffective in altering the onset of the circadian corticosterone rhythm.

Corticosterone Rhythmicity in the Rat: Interactive Effects of Dietary Restriction and Schedule of Feeding

Effects of changes in diet composition and schedule of restricted feeding on the circadian rhythm of plasma corticosterone in the adult rat were examined. Three restricted feeding schedules were used: diet presented 3 hours after lights-on, 1 hour before lights-off or continuously by automated feeder. Animals were paired to controls (consuming 24% protein diet ad libitum) and provided 80% of control food intake/g body weight/day. A fourth experimental group was offered 2.4% protein diet ad libitum. Plasma corticoids were measured every 4 hours from 0800 to 0400 hours. Corticoid levels 20 min after food presentation were also determined. Both control and protein-restricted animals displayed a typical circadian rhythm, with corticoids lowest at 0800 hours and a peak at 2000 hours. Animals fed at 0900 hours exhibited a 12-hour shift in peak corticoids, while the circadian rhythm was totally abolished in animals fed by automated feeder. Offering the restricted ration at 1700 hours, however, resulted in a diurnal rhythm similar to that of controls. While pre and post-feeding corticoids were similar in control and protein-restricted animals, a post-feeding suppression was found in all three food-restricted groups. Clearly, the relationship between feeding schedule and diurnal rhythm must not be ignored in nutritional paradigms.calorie restriction circadian rhythm corticosterone

Effect of intrahypothalamic implantation of cortisone acetate on the onset of circadian corticosterone rhythm in neonatal female rats.

Subcutaneous administration of corticosteroids to neonatal rats has been reported to delay the onset of the circadian corticosterone rhythm. Micropellets of a cortisone acetate(CA)-paraffin mixture or paraffin alone were implanted intrahypothalamically or subcutaneously in 2-day-old female rats. 24- or 48-hour patterns of blood corticosterone were obtained serially in individual rats at 21, 28, 35, 56 and 120 days of age. Sham(paraffin)-implanted rats and those bearing CA pellets subcutaneously showed a well-defined circadian corticosterone rhythm at day 28. CA implantation into the anterior hypothalamus, however, caused a delay in the onset of the circadian corticosterone rhythm by 1 week together with a diminished amplitude. In rats with CA pellets in the medial basal hypothalamus, the corticosterone rhythm was not fully established even on day 56, but was evident in most animals on day 120. It is suggested that neonatal CA treatment exerts its effect by inhibiting the maturation of the efferent neural pathways carrying circadian signals from the suprachiasmatic nuclei.

Serotoninergic system and circadian rhythms of ACTH and corticosterone in rats.

The circadian rhythms of plasma ACTH and corticosterone and of locomotor activity were explored in chronically cannulated female rats, after elimination of serotoninergic (5HT) innervation of the SCN (suprachiasmatic nuclei) either by stereotaxic lesion of the median and dorsal midbrain raphe nuclei (RX) or by local injection of SCN with the neurotoxin 5,7-dihydroxytryptamine (5,7DHT). Completeness of 5HT denervation was checked on serial sections of the hypothalamus either by the Falk-Hillarp technique or by radioautography. Neither lesion eliminated the intrahypothalamic 5HT system, which, however does not take part in the 5HT innervation of the SCN. In both experimental series, the circadian rhythms of the three parameters investigated were maintained in unchanged phase relationships compared to the sham-lesioned controls, and with respect to the photoperiod (12 light-12 dark). However, the estimated amplitudes of the ACTH rhythms dropped by 43% (RX) to 47% (5,7DHT) and their mean levels by 44% (RX) to 60% (5,7DHT), whereas the corticosterone rhythm displayed normal amplitude and its mean level rose by 24% (RX) or 38% (5,7DHT). In regard to locomotor activity rhythm, the most noticeable alteration was a 25-55% increase in the light-phase activity of both experimental groups with a correlative increase in the L/D activity ratio. The essential role of 5HT innervation of the SCN therefore seems to be to facilitate circadian control of the ACTH rhythm.

Effect of starvation on the circadian adrenocortical rhythm in rats.

The circadian rhythm of blood corticosterone was examined in rats whose feeding was restricted to a specific time of day. The peak of the corticosterone level was found just before feeding time regardless of whether, the rats were kept on a 12-h light, 12-h dark cycle or in constant light or were blinded. It took at least 10 days to establish the corticosterone rhythm corresponding to the feeding time, but once it had been established, it persisted for at least 2 days of stravation regardless of the lighting condition. It is concluded that the corticosterone rhythm entrained by food is endogenous.

Ontogeny of circadian corticosterone rhythm in female rats: effects of periodic maternal deprivation and food restriction.

The effects of maternal deprivation and food restriction on the ontogeny of the circadian blood corticosterone rhythm were studied. Control rats were normally mothered, weaned on day 23, and allowed to eat ad libitum. Experimental rats were subjected to 12 h of periodic maternal deprivation during either the day or night beginning on day 3. After weaning, they were either continued on food restriction or fed ad libitum. The daily corticosterone patterns were determined serially at 15, 20, 25, 30, and 35 days of age in individual rats. At 20 days of age, only maternally deprived rats showed corticosterone variations. Although peaks coinciding with the suckling period were observed in only half of the animals, all pups raised by the same mother showed similar corticosterone profiles. Late (day 16) onset of maternal deprivation or maternal deprivation in neonatally blinded pups did not cause such corticosterone fluctuations on day 20. In sighted rats raised by daytime suckling, nocturnal feeding appeared the...