Central nervous system mediation of pituitary adrenal rhythmicity.

Evidence favoring the view that there is a dissociation between the two aspects of pituitary adrenal operation, the stress and the rhythm modes, is as follows 1) it is possible to abolish rhythmic function by anterior hypothalamic lesions without altering the responses to stress; 2) during maturation of the rat CNS, the stress response appears prior to weaning while pituitary-adrenal rhythm appears after weaning; 3) appropriate neuropharmacologic treatment can block circadian rhythm without altering the stress response; 4) responsiveness to ether or immobilization may be independent of the diurnal rhythm; 5) the stress response to a very strong stimulus, such as immobilization, habituates while the circadian rhythm does not. On the other hand there is some evidence in favor of interdependence between the two modes of operation: 1) input channels for stress and rhythm may overlap since strong synchronizers of rhythm, such as food and water restriction and light can become stress stimuli; 2) steroid feedback can alter the timing of the circadian rhythm; 3) circadian variation has been observed in the responses to certain stimuli; 4) neurotransmitters which are prominently implicated in the circadian rhythm also appear involved in the stress response.     

Interactions between dopamine and melatonin organize circadian rhythmicity in the retina of the green iguana

Circadian physiology in the vertebrate retina is regulated by several neurotransmitters. In the lateral eyes of the green iguana the circadian rhythm of melatonin content peaks during the night while the rhythm of dopamine peaks during the day. In the present work, the authors explore the interaction of these 2 neurotransmitters during the circadian cycle. They depleted retinal dopamine with intravitreal injections of 6-hydroxydopamine (6-OHDA) and measured ocular melatonin content in vivo throughout 1 circadian cycle. The circadian rhythm of ocular melatonin not only persisted but increased 10-fold in amplitude. This increase was substantially reduced by the intraocular administration of dopamine. 6-OHDA-treated retinas, unlike those from untreated animals, did not express a circadian rhythm of melatonin synthesis in vitro. To deplete retinal melatonin, the authors pinealectomized iguanas and blocked retinal melatonin synthesis by depleting serotonin with intraocular injections of 5,6-dihydroxytryptamine. In animals so treated, they found that the circadian rhythm of retinal dopamine content was abolished, the levels of dopamine were lowered, and the levels of dopamine metabolites were greatly increased. The data suggest that in iguanas, the amplitude of the circadian rhythm of melatonin synthesis in the eye is suppressed by dopamine while the rhythm of dopamine depends, at least in part, on the presence of melatonin.     

Circadian Adrenocortical Periodicity Changes in Adult Rats Stimulated During Early Development—I. Effect of Prednisolone

The aim of this study was to test the feasibility of manipulating the adrenocortical circadian rhythm in adult rats by early postnatal prednisolone treatment. Prednisolone, when injected at 7-9 or 17-19 days after birth, produced a permanent suppression of the circadian rhythm of the basal levels of plasma 11-OH-corticosteroids and the rhythm of its responsiveness to stress. The administration of prednisolone at age of 2-4 or 12-14 days did not affect the circadian adrenocortical patterns in adults. Evidence was obtained for the existence of two critical periods during early development. Stimulation with prednisolone during these periods caused a profound modification of circadian periodicity in the performance of the pituitary-adrenocortical system. This modification was not related to changes in adrenal cortex ACTH responsiveness and also to altered stress reactivity of the pituitary-adrenocortical system. It was the presumable consequence of a blockage of a regulatory central mechanism initiating circadian variations in the pituitary-adrenocortical function. The existence of two distinct critical periods suggests that some prednisolone-sensitive links of this central pacemaker mechanism mature asynchronously during early postnatal life.     

Circadian Adrenocortical Periodicity Changes in Adult Rats Stimulated During Early Development—I. Effect of Prednisolone

The aim of this study was to test the feasibility of manipulating the adrenocortical circadian rhythm in adult rats by early postnatal prednisolone treatment. Prednisolone, when injected at 7-9 or 17-19 days after birth, produced a permanent suppression of the circadian rhythm of the basal levels of plasma 11-OH-corticosteroids and the rhythm of its responsiveness to stress. The administration of prednisolone at age of 2-4 or 12-14 days did not affect the circadian adrenocortical patterns in adults. Evidence was obtained for the existence of two critical periods during early development. Stimulation with prednisolone during these periods caused a profound modification of circadian periodicity in the performance of the pituitary-adrenocortical system. This modification was not related to changes in adrenal cortex ACTH responsiveness and also to altered stress reactivity of the pituitary-adrenocortical system. It was the presumable consequence of a blockage of a regulatory central mechanism initiating circadian variations in the pituitary-adrenocortical function. The existence of two distinct critical periods suggests that some prednisolone-sensitive links of this central pacemaker mechanism mature asynchronously during early postnatal life.     

Effect of fasting on the circadian rhythm of serum insulin levels.

The effects of 29 hrs of fast on gastric content, serum glucose and IRI levels were studied twice in normal mice. Both experiments showed a circadian rhythm of all parameters studied in control animals. Fasting in both experiments was unable to modify the circadian rhythm of gastric content and serum glucose levels, in spite of substantial modifications in their absolute values. Conversely, while the rhythm of serum IRI levels was not changed in one experiment, the other showed a variation with no level of significance. The latter coincides with the greatest decrease of both gastric content and serum glucose levels. Therefore, circadian IRI levels should be only within some range under the control of food intake. This suggests the possible existence of a threshold for absolute glucose and/or gastric content variation under which serum IRI level rhythm is unable to reach the level of significance.     

Circadian Rhythm of Liver Parameters (Cellular Structures, Mitotic Activity, Glycogen and Lipids in Liver and Serum) During Three Consecutive Cycles in Phenobarbital-Treated Rats

The circadian rhythm of gastric content, serum alkaline phosphatase (alk.P.), serum lipids, body weight (wt), relative (rel.) liver wt, cellular structures (by light- and electron-microscopy), mitotic activity of hepatocytes, glycogen content, protein and lipids in liver was studied in 180 male Sprague-Dawley rats orally treated at 0830-1030 with 50 mg/kg phenobarbital (PB) for 7 days. Thereafter, five PB-treated males and five controls each were studied at 4-hr intervals at 0600, 1000, 1400, 1800, 2200 and 0200 on 3 consecutive days. The lighting schedule in the colony was 12:12 = light/dark (light from 0600 to 1800). Following the rhythm of gastric emptying, the rel. liver wt showed a clear circadian rhythm with a peak at 0800. The rel. liver wt was raised in PB-treated rats at all times of the day. The circadian rhythm of cellular structures was closely related to the hepatic glycogen content which exhibited a clear rhythm with the peak also at 0800, but lowered values were found in PB-treated rats. The mitotic activity of hepatocytes was significantly increased in PB-treated rats but displayed the same circadian rhythm as controls with peaks at noon and troughs at midnight. The well-known hypertrophy of the smooth endoplasmic reticulum in PB-treated rats was not found at 0600, but was fully developed at 1400 and 2200. PB-treatment increased significantly the liver content of cholesterol, triglycerides and phospholipids. Liver cholesterol showed a clear circadian rhythm with peaks at 1800. No rhythm of liver protein, triglycerides and phospholipids was observed. In serum, levels of cholesterol were significantly elevated, those of triglycerides and alk.P. significantly lowered, while those of phospholipids were not affected by the treatment. The three serum lipids, alk.P. and beta-lipoprotein exhibited a clear circadian rhythm, while serum glucose and non-esterified fatty acids did not.     

Circadian Rhythm of Liver Parameters (Cellular Structures,Mitotic Activity,Glycogen and Lipids in Liver and Serum) During Three Consecutive Cycles in Phenobarbital-Treated Rats

The circadian rhythm of gastric content, serum alkaline phosphatase (alk.P.), serum lipids, body weight (wt), relative (rel.) liver wt, cellular structures (by light- and electron-microscopy), mitotic activity of hepatocytes, glycogen content, protein and lipids in liver was studied in 180 male Sprague-Dawley rats orally treated at 0830-1030 with 50 mg/kg phenobarbital (PB) for 7 days. Thereafter, five PB-treated males and five controls each were studied at 4-hr intervals at 0600, 1000, 1400, 1800, 2200 and 0200 on 3 consecutive days. The lighting schedule in the colony was 12:12 = light/dark (light from 0600 to 1800). Following the rhythm of gastric emptying, the rel. liver wt showed a clear circadian rhythm with a peak at 0800. The rel. liver wt was raised in PB-treated rats at all times of the day. The circadian rhythm of cellular structures was closely related to the hepatic glycogen content which exhibited a clear rhythm with the peak also at 0800, but lowered values were found in PB-treated rats. The mitotic activity of hepatocytes was significantly increased in PB-treated rats but displayed the same circadian rhythm as controls with peaks at noon and troughs at midnight. The well-known hypertrophy of the smooth endoplasmic reticulum in PB-treated rats was not found at 0600, but was fully developed at 1400 and 2200. PB-treatment increased significantly the liver content of cholesterol, triglycerides and phospholipids. Liver cholesterol showed a clear circadian rhythm with peaks at 1800. No rhythm of liver protein, triglycerides and phospholipids was observed. In serum, levels of cholesterol were significantly elevated, those of triglycerides and alk.P. significantly lowered, while those of phospholipids were not affected by the treatment. The three serum lipids, alk.P. and beta-lipoprotein exhibited a clear circadian rhythm, while serum glucose and non-esterified fatty acids did not.     

Activity in the ferret: oestradiol effects and circadian rhythms

The present study was conducted to determine whether oestradiol increases activity in the European ferret (Mustela furo), whether this effect is sexually dimorphic, and whether a 24-h rhythm is present in the ferret's daily activity. The activity of male and female adult, postpubertally gonadectomized ferrets was monitored while they were maintained singly on a 13:11 light-dark cycle, before and after implantation with oestradiol-17β. Gonadectomized male and female ferrets exhibited equal levels of activity, and neither sex exhibited a significant change in activity following oestradiol implantation. None of the ferrets exhibited a strong circadian rhythm, although weak 24-h rhythms and shorter harmonic rhythms were present. Golden hamsters (Mesocricetus auratus), monitored in an identical manner, exhibited strong circadian rhythms. It was concluded that oestradiol administration may not cause an increase in activity in the ferret, and that this species lacks a strong circadian activity rhythm.     

On analyzing circadian rhythms data using nonlinear mixed models with harmonic terms

Wang, Ke, and Brown (2003, Biometrics59, 804-812) developed a smoothing-based approach for modeling circadian rhythms with random effects. Their approach is flexible in that fixed and random covariates can affect both the amplitude and phase shift of a nonparametrically smoothed periodic function. In motivating their approach, Wang et al. stated that a simple sinusoidal function is too restrictive. In addition, they stated that "although adding harmonics can improve the fit, it is difficult to decide how many harmonics to include in the model, and the results are difficult to interpret." We disagree with the notion that harmonic models cannot be a useful tool in modeling longitudinal circadian rhythm data. In this note, we show how nonlinear mixed models with harmonic terms allow for a simple and flexible alternative to Wang et al.'s approach. We show how to choose the number of harmonics using penalized likelihood to flexibly model circadian rhythms and to estimate the effect of covariates on the rhythms. We fit harmonic models to the cortisol circadian rhythm data presented by Wang et al. to illustrate our approach. Furthermore, we evaluate the properties of our procedure with a small simulation study. The proposed parametric approach provides an alternative to Wang et al.'s semiparametric approach and has the added advantage of being easy to implement in most statistical software packages.     

Circadian clock functioning is linked to acute stress reactivity in rats

At least two major physiological systems are involved in the adaptation of the organism to environmental challenges: the circadian system and the stress reaction. This study addressed the possibility that interindividual differences in stress sensitivity and in the functioning of the circadian system are related. At 2 months of age, corticosterone secretion in response to a 20-min restraint stress was assessed in 9 Sprague-Dawley rats for which running wheel activity was recorded as a rhythmic behavioral marker of the circadian clock. Two weeks later, the adaptive response of the circadian system to an abrupt shift in the light:dark (LD) cycle was assessed in those rats using a jet-lag paradigm. Finally, after resynchronization to the new LD cycle, rats were transferred to constant darkness to assess the free-running period of their circadian rhythm of running-wheel activity. Results indicate that stress-induced corticosterone secretion was (1) positively correlated with the number of days to resynchronize the circadian activity rhythm to the new LD cycle, and with the value of its free-running period, and (2) negatively correlated with the intensity of daily locomotor activity. Those data, emphasizing the interactions between the stress response of an organism and the functioning of its circadian system, could explain interindividual differences in humans' susceptibility to shift work or other circadian-related disorders.     

Circadian rhythmicity in substance use disorder male patients with and without comorbid depression under ambulatory and therapeutic community treatment

Although there have been described alterations of circadian rhythmicity both in patients with substance use disorder (SUD) and patients with major depressive disorder (MDD), the circadian characteristics of SUD patients with comorbid MDD (SUD-MDD) are unknown. Likewise, the possible influence of the different modalities of treatments (ambulatory or therapeutic community) upon the circadian rhythmicity of SUD patients has not been characterized. Therefore, this study analyzes the circadian rhythmic profiles of SUD and SUD-MDD patients under ambulatory and therapeutic community treatment. The sample was composed of 40 SUD and 40 SUD-MDD men, aged 22–55 yrs, under treatment and with abstinence for at least three months (including each group 20 ambulatory and 20 from therapeutic community). Patients completed a sociodemographic, clinical and sleep-wake schedules interview, the Composite Scale of Morningness, and wore on the wrist an ambulatory device known as iButton® Thermochron DS1921H, which registered their distal skin temperature every two minutes for 48 hours. All the groups showed a tendency to morningness without differences among them in concordance with their sleep-wake schedules. With regard to distal skin temperature circadian rhythm, SUD patients showed higher values than SUD-MDD in amplitude, relative amplitude, percentage rhythm, and first harmonic power, and lower minimum temperature in 10 consecutive hours (p < .043, in all cases). Therapeutic community group values were lower in minimum temperature and higher in amplitude, relative amplitude, and 12 harmonic accumulated power (p < .028, in all cases) as compared to ambulatory ones. Moreover, all groups showed higher Rayleigh vector and rhythm stability as compared to normative population (p < .043, in both cases). The circadian rhythmic differences observed for diagnosis and type of treatment are indicative of a higher circadian rhythmicity robustness in SUD and therapeutic community patients as compared to SUD-MDD and ambulatory ones, respectively. Although drug consumption exerts a negative effect on the circadian rhythmicity, our results (high amplitude and rhythm stability) are indicative of an adequate circadian functioning as well as of an adjustment to the light-dark cycle in both diagnosis and type of treatment which may constitute a marker of the adherence to treatment and recovery status.     

Role of brain noradrenergic mechanisms in disturbing the circadian rhythm of the functioning hypothalamo-hypophyseo-adrenal cortex system in white rats in early ontogeny

The effects of hormone action and disturbance in catecholamine synthesis in the early postnatal ontogenesis on the circadian rhythm in the hypothalamic-hypophysial-adrenocortical system function were compared in the adult albino rat males. Injection of prednisolone on the 17-19th days of life blocked completely the diurnal rhythm of the corticosterone basal level in blood, the rhythm of adrenocortical response to an emotional stressor and to injection of noradrenaline into the brain lateral ventricle in 3-4 month old animals. Injection of an inhibitor of tyrosine hydroxylase, alpha-methyl-p-tyrosine, at the same period resulted in disappearance of the diurnal rhythm of the corticosterone basal level in adult animals, although the rhythm of response to an emotional stressor or injection of noradrenaline into the brain remained unchanged. A conclusion has been reached that disturbances in catecholamine synthesis in the early postnatal period induces long-term changes of predominantly tonic corticosterone secretion, while the hormone action on the circadian rhythm of the corticosterone basal level and stress response is only partly due to changes in noradrenergic regulation of the hypothalamic-hypophysial-adrenocortical system.     

Circadian rhythmicity of vasopressin levels in the cerebrospinal fluid of suprachiasmatic nucleus-lesioned and -grafted rats

Transplantation of the fetal suprachiasmatic nucleus (SCN) in arrhythmic SCN-lesioned rats can reinstate circadian drinking rhythms in 40% to 50% of the cases. In the current article, it was investigated whether the failure in the other rats could be due to the absence of a circadian rhythm in the grafted SCN, using a circadian vasopressin (VP) rhythm in the cerebrospinal fluid (CSF) as the indicator for a rhythmic SCN. CSF was sampled in continuous darkness from-intact control rats and SCN-lesioned and -grafted rats. VP could be detected in all samples, with concentrations of 15 to 30 pg/ml in the control rats and 5 to 15 pg/ml in the grafted rats. A circadian VP rhythm with a two- to threefold difference between peak and nadir values was found in all 7 control rats but in only 4 of 13 experimental rats, despite the presence of a VP-positive SCN in all grafts. A circadian VP rhythm was present in 2 drinking rhythm-recovered rats (6 of 13) and in 2 nonrecovery rats. Apparently, in these latter rats, the failure of the grafted SCN to restore a circadian drinking rhythm cannot be attributed to a lack of rhythmicity in the SCN itself. Thus, the presence of a rhythmic grafted SCN, as is deduced from a circadian CSF VP rhythm, appears not to be sufficient for restoration of a circadian drinking rhythm in SCN-lesioned arrhythmic rats.     

Circadian rhythm in melatonin release as a mechanism to reinforce the temporal organization of the circadian system in crayfish

Melatonin (MEL) is a conserved molecule with respect to its synthesis pathway and functions. In crayfish, MEL content in eyestalks (Ey) increases at night under the photoperiod, and this indoleamine synchronizes the circadian rhythm of electroretinogram amplitude, which is expressed by retinas and controlled by the cerebroid ganglion (CG). The aim of this study was to determine whether MEL content in eyestalks and CG or circulating MEL in hemolymph (He) follows a circadian rhythm under a free-running condition; in addition, it was tested whether MEL might directly influence the spontaneous electrical activity of the CG. Crayfish were maintained under constant darkness and temperature, a condition suitable for studying the intrinsic properties of circadian systems. MEL was quantified in samples obtained from He, Ey, and CG by means of an enzyme-linked immunosorbent assay, and the effect of exogenous MEL on CG spontaneous activity was evaluated by electrophysiological recording. Variation of MEL content in He, Ey, and CG followed a circadian rhythm that peaked at the same circadian time (CT). In addition, a single dose of MEL injected into the crayfish at different CTs reduced the level of spontaneous electrical activity in the CG. Results suggest that the circadian increase in MEL content directly affects the CG, reducing its spontaneous electrical activity, and that MEL might act as a periodical signal to reinforce the organization of the circadian system in crayfish.     

Left and right brain hemispheres in the regulation of pain sensitivity biorhythms in mice during stress

The foot-shock effects on ultradian and circadian rhythms of pain sensitivity in the SHR mice were studied after unilateral brain cortex hemisphere inactivation by means of the Leao spreading depression. Under acute painful stress, the left hemisphere partially loses its synchronizing effect on circadian rhythm and supports the 12-hour and particularly 6-hour periodicities. The left hemisphere effect dominates in intact animals under stress. The right hemisphere under the same conditions mainly loses its activating effect on circadian rhythm and supports the 8- and 16-hour periodicities. The right hemisphere effect dominates in animals under stress operated 2-3 days prior to the experiment.     

Circadian variation in methotrexate toxicity in streptozotocin-induced diabetes mellitus rats

The effects of diabetes mellitus and circadian rhythm on pharmacokinetics or pharmacodynamics of drugs have been previously separately reviewed. In our previous study, a circadian rhythm has been described in the pharmacokinetics of MTX in streptozotocin-induced diabetes mellitus (SIDM) rats. The aim of the present study was to investigate the effects of circadian rhythm on the toxicity of MTX in SIDM rats. The hematologic parameters and serum folic acid levels were measured in control and SIDM groups before and after MTX administration to evaluate its toxicity. We observed that circadian rhythm in basal peripheral WBC counts disappeared after MTX administration in the first hour and were phase shifted on the fifth day. Circadian variations were not observed in the other blood cells. One hour after MTX administration, folic acid levels were high in both groups. However, a circadian rhythm was present only in the diabetic group. The alteration in the rhythm of WBC counts in diabetic rats may originate not only from the effect of MTX but also physiological alterations due to diabetes and/or the varying cell cycle entry rates in the hematopoetic stem cells.     

Possible involvement of nitric oxide in generation of orcadian rhythm

Abstract

The effect of continuous infusion of N^G‐methylarginine, an inhibitor of nitric oxide synthase, into the third cerebral ventricle above the suprachiasmatic nucleus (SCN) of the hypothalamus on the circadian rhythm of water intake was examined in rats maintained under either a 12‐h light and 12‐h dark cycle or in constant darkness. N^G‐methylarginine disrupted the circadian rhythm in both conditions. In constant darkness, however, the effect of the inhibitor on the rhythm was found to be due to change in its phase. These findings suggest that nitric oxide is involved in the mechanism of the generation and/or synchronization of the circadian rhythm driven by the circadian oscillator in the SCN.     

Study of autacoids role in the regulation of circadian rhythm of the human renal function

The circadian rhythm of urine formation was studied in younger (27 +/- 8 yr) and aged (76 +/- 3 yr) males. In 11 younger healthy examined persons a decrease of diuresis during the night as compared with the day time was due to a rise of solute free water reabsorption. In 31 aged males the change of the urine formation rhythm with increase of the nocturnal diuresis is based on a rise of osmolal clearance combined with an increase of the solute free water reabsorption. It is shown that blockade of autacoid secretion leads to normalization of the diuresis circadian rhythm. In 10 aged men, nocturia was due to a decrease of vasopressin secretion which resulted in a decrease of the solute free water reabsorption and an increase of diuresis. The obtained data are considered as an evidence for the role of renal autacoids, alongside with vasopressin, in regulation of the circadian rhythm of the kidney function.     

A statistical model of the human core-temperature circadian rhythm

We formulate a statistical model of the human core-temperature circadian rhythm in which the circadian signal is modeled as a van der Pol oscillator, the thermoregulatory response is represented as a first-order autoregressive process, and the evoked effect of activity is modeled with a function specific for each circadian protocol. The new model directly links differential equation-based simulation models and harmonic regression analysis methods and permits statistical analysis of both static and dynamical properties of the circadian pacemaker from experimental data. We estimate the model parameters by using numerically efficient maximum likelihood algorithms and analyze human core-temperature data from forced desynchrony, free-run, and constant-routine protocols. By representing explicitly the dynamical effects of ambient light input to the human circadian pacemaker, the new model can estimate with high precision the correct intrinsic period of this oscillator ( approximately 24 h) from both free-run and forced desynchrony studies. Although the van der Pol model approximates well the dynamical features of the circadian pacemaker, the optimal dynamical model of the human biological clock may have a harmonic structure different from that of the van der Pol oscillator.