Sleep-activity Cycle Research Articles

Postnatal outcomes in lambs exposed antenatally and acutely postnatally to fluoxetine.

Approximately 1/3 of newborns exposed antenatally to selective serotonin reuptake inhibitors (SSRIs) exhibit poor neonatal adaptation. Although several potential mechanisms have been proposed, the actual mechanism has not been elucidated. We investigated outcomes in neonatal lambs exposed prenatally or postnatally to fluoxetine (FX). Daily FX injections (50 mg) were given intravenously (i.v.) to five pregnant ewes via implanted catheters beginning at 131-132 days gestation (term = 147 days) for 2 weeks. In another group, lambs with implanted vascular catheters had sterile water (n = 9) or FX (1 mg/kg, n = 12) injected i.v. on ~postnatal day (PND) 4. Prenatal FX-exposed lambs (n = 7) were hyperactive during PND 4 to 14 and their heart rate variability (HRV) was significantly lower than in control lambs (n = 7) on PND 2. In contrast, arterial pressure, heart rate, electrocardiogram, arterial blood gases, pH, glucose, lactate, cortisol, and sleep-activity cycles were not altered following postnatal FX injection. This abnormal postnatal hyperactivity with antenatal FX exposure may reflect increased maturity in terms of locomotory activity. The results suggest that altered brain development may be involved in the poor neonatal adaptation in human infants exposed to FX in utero.

Manipulations of amyloid precursor protein cleavage disrupt the circadian clock in aging Drosophila

Alzheimer's disease (AD) is a neurodegenerative disease characterized by severe cognitive deterioration. While causes of AD pathology are debated, a large body of evidence suggests that increased cleavage of Amyloid Precursor Protein (APP) producing the neurotoxic Amyloid-β (Aβ) peptide plays a fundamental role in AD pathogenesis. One of the detrimental behavioral symptoms commonly associated with AD is the fragmentation of sleep-activity cycles with increased nighttime activity and daytime naps in humans. Sleep-activity cycles, as well as physiological and cellular rhythms, which may be important for neuronal homeostasis, are generated by a molecular system known as the circadian clock. Links between AD and the circadian system are increasingly evident but not well understood. Here we examined whether genetic manipulations of APP-like (APPL) protein cleavage in Drosophila melanogaster affect rest-activity rhythms and core circadian clock function in this model organism. We show that the increased β-cleavage of endogenous APPL by the β-secretase (dBACE) severely disrupts circadian behavior and leads to reduced expression of clock protein PER in central clock neurons of aging flies. Our data suggest that behavioral rhythm disruption is not a product of APPL-derived Aβ production but rather may be caused by a mechanism common to both α and β-cleavage pathways. Specifically, we show that increased production of the endogenous Drosophila Amyloid Intracellular Domain (dAICD) caused disruption of circadian rest-activity rhythms, while flies overexpressing endogenous APPL maintained stronger circadian rhythms during aging. In summary, our study offers a novel entry point toward understanding the mechanism of circadian rhythm disruption in Alzheimer's disease.

Validation of actigraphy to assess circadian organization and sleep quality in patients with advanced lung cancer

BackgroundMany cancer patients report poor sleep quality, despite having adequate time and opportunity for sleep. Satisfying sleep is dependent on a healthy circadian time structure and the circadian patterns among cancer patients are quite abnormal. Wrist actigraphy has been validated with concurrent polysomnography as a reliable tool to objectively measure many standard sleep parameters, as well as daily activity. Actigraphic and subjective sleep data are in agreement when determining activity-sleep patterns and sleep quality/quantity, each of which are severely affected in cancer patients. We investigated the relationship between actigraphic measurement of circadian organization and self-reported subjective sleep quality among patients with advanced lung cancer.MethodsThis cross-sectional and case control study was conducted in 84 patients with advanced non-small cell lung cancer in a hospital setting for the patients at Midwestern Regional Medical Center (MRMC), Zion, IL, USA and home setting for the patients at WJB Dorn Veterans Affairs Medical Center (VAMC), Columbia, SC, USA. Prior to chemotherapy treatment, each patient's sleep-activity cycle was measured by actigraphy over a 4-7 day period and sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire.ResultsThe mean age of our patients was 62 years. 65 patients were males while 19 were females. 31 patients had failed prior treatment while 52 were newly diagnosed. Actigraphy and PSQI scores showed significantly disturbed daily sleep-activity cycles and poorer sleep quality in lung cancer patients compared to healthy controls. Nearly all actigraphic parameters strongly correlated with PSQI self-reported sleep quality of inpatients and outpatients.ConclusionsThe correlation of daily activity/sleep time with PSQI-documented sleep indicates that actigraphy can be used as an objective tool and/or to complement subjective assessments of sleep quality in patients with advanced lung cancer. These results suggest that improvements to circadian function may also improve sleep quality.

The normalization of the cortisol awakening response and of the cortisol shift profile across consecutive night shifts—An experimental study

This study tested the hypothesis that the cortisol awakening response (CAR) and the cortisol shift profile normalize with successive night shifts due to the shift of the circadian system. 18 students (9 women, 9 men, 19-29 years), worked first four consecutive morning- and then four consecutive night shifts. Each work shift was preceded by an 8-h sleep opportunity meaning that the sleep-activity cycle was advanced by 8 h. The advance of the circadian system was promoted by a 2-h bright light pulse at the end of each night shift and quantified by 24-h phase assessment procedures (PA) before and after the four day shifts and again after the four night shifts. Saliva samples were taken 0, 15, 30, 45, and 60 min post-awakening, hourly during each work shift and each PA. During the night shift sequence, the CAR, indicated by the area under curve with respect to increase (AUC(I)), increased gradually across the 4-day sleep periods. Baseline levels were reached after 3 days in men and 4 days in women. The increase of the CAR was associated with a gradually increasing decline of cortisol levels during the night shifts. This adjustment was--at least not only--related to the advance of the circadian system which was 5 h. A contributor to the increase of the CAR might be the anticipation of the upcoming demands of the following work shifts.

Dopamine transporter-related effects of modafinil in rhesus monkeys

Modafinil is currently used as a treatment for daytime sleepiness. The objectives of this study were to explore the dopamine transporter (DAT)-related effects of modafinil on behavior and in vivo neurochemistry in rhesus monkeys (Macaca mulatta). The effects of modafinil (3.0-10 mg/kg, i.v.) were evaluated on locomotor activity, reinstatement of cocaine-maintained behavior, extracellular dopamine levels in the caudate nucleus, and DAT occupancy in the dorsal striatum. Eight subjects were fitted with a collar-mounted activity monitor to evaluate sleep-activity cycles, with 4 days of baseline recording preceding an injection of saline or modafinil (3.0-10 mg/kg). The effects of modafinil (3.0-10 mg/kg) and cocaine (0.3 mg/kg) on reinstatement of behavior that was previously maintained under a second-order schedule of i.v. cocaine delivery were tested in a separate group of subjects (n = 6). Finally, the effects of modafinil (3.0-10 mg/kg) on extracellular dopamine levels and DAT occupancy in vivo were characterized using microdialysis and positron emission tomography, respectively, in a within-subjects design (n = 4). Modafinil significantly increased nighttime locomotor activity and reinstated cocaine-maintained behavior but did not affect daytime locomotor activity. Modafinil significantly increased striatal extracellular dopamine levels at a dose that resulted in DAT occupancy of 64.4% (putamen) and 60.2% (caudate). The behavioral and in vivo dopaminergic effects of modafinil are consistent with the profile of a low potency DAT inhibitor and may indicate potential for abuse at high doses.

Regulation of circadian blood pressure: from mice to astronauts

Circadian variation is commonly seen in healthy people; aberration in these biological rhythms is an early sign of disease. Impaired circadian variation of blood pressure (BP) has been shown to be associated with greater target organ damage and with an elevated risk of cardiovascular events independent of the BP load. The purpose of this review is to examine the physiology of circadian BP variation and propose a tripartite model that explains the regulation of circadian BP. The time-keeper in mammals resides centrally in the suprachiasmatic nucleus. Apart from this central clock, molecular clocks exist in most peripheral tissues including vascular tissue and the kidney. These molecular clocks regulate sodium balance, sympathetic function and vascular tone. A physiological model is proposed that integrates our understanding of molecular clocks in mice with the circadian BP variation among humans. The master regulator in this proposed model is the sleep-activity cycle. The equivalents of peripheral clocks are endothelial and adrenergic functions. Thus, in the proposed model, the variation in circadian BP is dependent upon three major factors: physical activity, autonomic function, and sodium sensitivity. The integrated consideration of physical activity, autonomic function, and sodium sensitivity appears to explain the physiology of circadian BP variation and the pathophysiology of disrupted BP rhythms in various conditions and disease states. Our understanding of molecular clocks in mice may help to explain the provenance of blunted circadian BP variation even among astronauts.

Aging, rhythms of physical performance, and adjustment to changes in the sleep-activity cycle.

OBJECTIVES: Shiftwork causes disturbances of the normal sleep-wake cycle and circadian rhythm. There is concern that aging workers have more problems than younger counterparts when the human body clock is...

Deriving a "phase response curve" from adjustment to simulated time zone transitions.

Thirty-eight subjects in groups of two to four have been subjected to simulated time zone transitions of 8 hr eastward, 8 hr westward, or 12 hr; all experiments have taken place in a temporal isolation unit, in which the light intensity during the waking periods was 250-300 lux. Circadian rhythms of rectal temperature have been used as a marker of the process of adjustment, the data being analyzed before (raw) and after "purification." Conventional results have been obtained, but when the data have been treated appropriately, they have produced a relationship between shift of the sleep-activity cycle and shift of the temperature rhythms that shows many characteristics of a phase response curve. Even though the factor or factors causing such adjustment are unknown, the results confirm that changes of a consonant set of "weak" zeitgebers is sufficient for entrainment to a new time zone to occur.

Do gonadal steroids regulate circadian rhythms in humans?

While a number of studies demonstrate that gonadal steroids regulate circadian rhythms in animal, the issue has received little attention in humans. The question is relevant to our understanding of gender differences in the phenomenology of depression, and of changes in the sleep-activity cycle that are seen in affective illness and during the menopause. In this paper, the literature demonstrating that gonadal steroids regulate circadian rhythms in animals is reviewed, along with the limited human literature. A hypothesis is forwarded suggesting that, in humans, estrogen shortens the circadian period, lengthens the sleep phase, advances sleep onset, and consolidates sleep. A study in progress is described which is designed to test the effects of the hypogonadal state, estrogen, and progesterone on circadian rhythms in women.

Circadian rhythm in the brain serotonin concentrations of the lizard, Anolis carolinensis

1. Whole brain serotonin content and concentration were determined in male and female lizards of the species Anolis carolinensis using a fluorimetric assay method based upon that described by Quay (1963). 2. Mean serotonin concentrations (μg/g wet weight of brain) in male lizards killed in May-June and August were as follows: 5·41±1·43 (S.D.) at 7.00 a.m., 1·83±1·00 at noon, 5·07±1·14 at 4.00 p.m. and 6·48±2·24 at midnight. 3. Mean serotonin concentrations for females killed in September were as follows: 3·82 at 7·00 a.m., 2·57 at noon, 3·71 at 4.00 p.m. and 7·68 at midnight. 4. No significant difference was found between males and females killed in the fall, but a definite circadian rhythm is indicated, there being a significant difference between the values found at noon and at midnight. 5. The highest concentration found was at midnight and the lowest at noon, suggesting a correlation with the animals' sleep-activity cycle and/or light regime.

Circadian periodicity of plasma 11-hydroxycorticosteroid levels in subjects with partial and absent light perception.

Abnormal circadian patterns of plasma corticosteroid levels were observed in 9 of 12 subjects with total absence of light perception and 5 of 7 subjects with partial absence of light perception secondary to intraocular disease. This abnormality consisted both of elevated levels at given times of day and a lack of reproducibility of the circadian pattern over 2 successive 24-hour periods. In 11 of 13 subjects with abnormal circadian periodicity, an early morning rise in plasma corticosteroid levels still occurred, though in 5 of these 11 subjects this rise occurred somewhat in advance of the usual 8 a.m. peak. This might indicate that the sleep-wake rather than dark-light transition plays a major role in the regulation of this phase of circadian periodicity. There was no correlation between the occurrence of abnormal patterns and either the age of the subject, age at onset or duration of blindness, or the subject’s sleep-activity cycle.

Circadian rhythms of plasma 17-hydroxycorticosteroids in the infant monkey.

SummaryPlasma 17-hydroxycorticosteroids (17-OHCS) exhibited a significant circadian rhythm in rhesus monkeys (M. mulatta) in the first week of life. In two experiments, plasma 17-OHCS levels averaged 35 μg/100 ml at 8-9:00 am, and declined to levels of 29 μg/100 ml at 9:00 pm (Expt. I) and 24 μg/100 ml at 12:00 midnight (Expt. II). These changes were about half the magnitude reported by others in the adult monkey. Correlated with this steroid rhythm, the infant monkey, although having a polyphasic 24-hr sleep pattern, also exhibited a tendency to sleep more at 1:00 and 3:00 am than at other times of the day. This suggested a relationship between sleep–activity cycles and steroid cycles in the infant monkey similar to that in the adult monkey.