Rest-activity Cycle Research Articles

Melanopsin retinal ganglion cell loss and circadian dysfunction in Alzheimer's disease (Review).

Alzheimer's disease affects 27 million individuals and is the most common cause of dementia worldwide. The pathology of Alzheimer's disease is primarily due to the β-amyloid deposits and neurofibrillary tangles. These deposits exist largely in the cerebral blood vessels, but have also been shown to exist in retinal vessels. A new class of cells that were recently identified, known as melanopsin-expressing retinal ganglion cells (mRGCs), are involved in the non-image forming functions of the eye. These functions include circadian activities such as temperature rhythms, melatonin release and rest-activity cycles. Circadian dysfunction has been investigated in many cases of Alzheimer's disease. In this review, we outline the current accepted Alzheimer's disease pathology, the role of mRCGs in optic neuropathies and the role of mRCGs, leading to circadian dysfunction, in Alzheimer's disease.

Behavioral Periodicity Detection from 24 h Wrist Accelerometry and Associations with Cardiometabolic Risk and Health-Related Quality of Life.

Periodicities (repeating patterns) are observed in many human behaviors. Their strength may capture untapped patterns that incorporate sleep, sedentary, and active behaviors into a single metric indicative of better health. We present a framework to detect periodicities from longitudinal wrist-worn accelerometry data. GENEActiv accelerometer data were collected from 20 participants (17 men, 3 women, aged 35–65) continuously for 64.4 ± 26.2 (range: 13.9 to 102.0) consecutive days. Cardiometabolic risk biomarkers and health-related quality of life metrics were assessed at baseline. Periodograms were constructed to determine patterns emergent from the accelerometer data. Periodicity strength was calculated using circular autocorrelations for time-lagged windows. The most notable periodicity was at 24 h, indicating a circadian rest-activity cycle; however, its strength varied significantly across participants. Periodicity strength was most consistently associated with LDL-cholesterol (r's = 0.40–0.79, P's < 0.05) and triglycerides (r's = 0.68–0.86, P's < 0.05) but also associated with hs-CRP and health-related quality of life, even after adjusting for demographics and self-rated physical activity and insomnia symptoms. Our framework demonstrates a new method for characterizing behavior patterns longitudinally which captures relationships between 24 h accelerometry data and health outcomes.

Pedunculopontine Gamma Band Activity and Development.

This review highlights the most important discovery in the reticular activating system in the last 10 years, the manifestation of gamma band activity in cells of the reticular activating system (RAS), especially in the pedunculopontine nucleus, which is in charge of waking and rapid eye movement (REM) sleep. The identification of different cell groups manifesting P/Q-type Ca2+ channels that control waking vs. those that manifest N-type channels that control REM sleep provides novel avenues for the differential control of waking vs. REM sleep. Recent discoveries on the development of this system can help explain the developmental decrease in REM sleep and the basic rest-activity cycle.

Fluctuation of blood glucose level in newborn rats depending on the season and spontaneous motor activity pattern

Previously, we demonstrated that in newborn rat pups the blood glucose level changes depending on the spontaneous periodic motor activity (SPMA) pattern. During rest periods, both under dominant decasecond and minute rhythms, the blood glucose level is higher than during activity periods. We also showed that the blood glucose level rises with age reaching the “adult” level by day 10. In the present study conducted on 3–10-day-old rat pups under free behavior conditions, the blood glucose level has been examined at different periods of the activity–rest cycle and at different seasons. It has been established that in newborn rats at all ages tested (3, 5, 7 and 10 days) the lowest glucose concentration occurs in winter. In spring, the glucose level increases reaching its maximum in summer when it is significantly different from those in winter and spring in all age groups except for day 5. In autumn, the glucose level decreases approaching its spring values but still differing significantly from the winter values. In 5-day-old rats, no significant changes in the glucose level at different seasons have been found. These data indicate seasonal fluctuations of the blood glucose level in newborn rats. Meanwhile, during all seasons except for spring the blood glucose level depends on the SPMA pattern. In spring, these differences are smoothed.

New multimodal data obtained in-vivo from a single ultra-miniature transducer.

Recent advances in multimodal sensing technology and sensor miniaturization technologies are paving the way for a new era in physiological measurement. Traditional approaches have integrated several transducers on a single silicon chip or packaged several sensing elements within a biocompatible catheter. Thermal and electrical cross-talk between sensors, time-lag between parallel measurements, lower yields associated with the increased complexity, and restrictions on the minimum size are challenges presented by these approaches. We present an alternative method which enables simultaneous measurement of temperature, pressure and heart rate to be obtained from a single ultra-miniature solid-state transducer. For the first time multimodal data were obtained from the sensor located within the abdominal aortas of five rats. The catheter-tip sensor interfaces with a fully implanted and inductively powered telemetry device capable of operating for the lifetime of the animal. Results of this study demonstrate good agreement between the core-temperature measurement from the catheter-tip sensor and the reference sensor with mean difference between the two sensors of 0.03 °C ± 0.02 °C (n = 5, 7 days). Real-time data obtained in the undisturbed rat, revealed fluctuations associated with the rest-activity cycle, in temperature, mean arterial pressure and heart rate. The stress response was shown to elicit an elevation in the core temperature of 1.5 °C. This was heralded by an elevation in mean arterial pressure of 35 mmHg and heart rate of 160 bpm. Obtaining multiple parameters from a single transducer goes a considerable way towards overcoming challenges of the prior art.

Antenatal cardiotocography: problems and facilitiies

The role of antenatal cardiotocography (CTG) in algorithm of fetal functional conditions disorders diagnosis is discussed in this article. Furthermore, visual and computer analysis of antenatal monitoring results have been compared. There were discussed Dawes-Redman criteria and based on them CTG systems of computer numeral analysis (Sonicaid System 8000, Sonicaid System 8002, Sonicaid FetalCare). There were shown that based principles of antenatal CTG registrations should be kept in any case, its analysis is possible only in time of active phase of the fetus rest-activity cycle. Any kind of questionable tracing should be analyzed by medical expert in special centers with appropriate experience.

Circadian typology and the Alternative Five-Factor Model of personality.

Two studies were carried out to explore the relationship between circadian typology and the Alternative Five-Factor Model of personality. In the first study, 379 participants (232 females) were administered the reduced version of the Morningness-Eveningness Questionnaire and the Zuckerman-Kuhlman Personality Questionnaire. Evening types reported higher impulsive sensation-seeking scores than morning and intermediate types, whereas morning types scored higher than evening types on activity factor. In the second study, the association between morningness and activity personality factor was verified through the objective-actigraphic monitoring of the rest-activity cycle. Actigraphy allowed us to operationalise both circadian typology, through the computing of midpoint of sleep (early values, expressed in hours and minutes, correspond to an advanced phase of the sleep/wake cycle), and activity factor by the means of motor activity recording. Fifty-one individuals (30 females) wore an actigraph on the nondominant wrist continuously for 1 week. A negative correlation was observed between midpoint of sleep and mean diurnal motor activity, demonstrating that an early phase of the sleep/wake cycle (i.e. morningness preference) was related to higher diurnal motor activity. Assessed both subjectively and objectively, the results of both studies highlight a significant relationship between morningness and activity personality factor.

The Zurich 3-step concept for the management of behavioral sleep disorders in children: a before-and-after study.

Several strategies have been found to be effective for the treatment of childhood behavioral sleep disorders. One which has yet to be evaluated is the Zurich 3-step concept, which combines basic notions of the two-process model of sleep regulation (introducing a regular rhythm and adjusting bedtime to sleep need) with behavioral strategies. This uncontrolled before-and-after study describes our concept and its step-wise approach, assesses changes in sleep-wake variables and behavior problems, and also examines associations between changes in sleep-wake variables and behavior problems. A total of 79 children with sleep problems (age range 6-47 months, 42% females) were included. Sleep problems were assessed by the Infant Sleep Questionnaire, sleep-wake variables by diary and actigraphy, and behavior problems of children ≥ 18 months by the Child Behavior Checklist. A significant decrease in nocturnal wake duration (Cohen's d = -0.34) and a significant increase in the duration of the longest continuous nocturnal sleep period (Cohen's d = 0.19) were found from before to after intervention (on average 2.7 months, SD 1.5). The variability for sleep onset and end time decreased, and actigraphically measured circadian rest-activity cycle measures improved. Parent-reported internalizing and total behavior problems also decreased (Cohen's d = 0.66). The findings of both objective and subjective assessment techniques suggest that the Zurich 3-step concept is effective. Thus, the intervention concept may be useful in clinical practice with sleep-disordered children.

Clock-Talk: Interactions between Central and Peripheral Circadian Oscillators in Mammals.

In mammals, including humans, nearly all physiological processes are subject to daily oscillations that are governed by a circadian timing system with a complex hierarchical structure. The central pacemaker, residing in the suprachiasmatic nucleus (SCN) of the ventral hypothalamus, is synchronized daily by photic cues transmitted from the retina to SCN neurons via the retinohypothalamic tract. In turn, the SCN must establish phase coherence between self-sustained and cell-autonomous oscillators present in most peripheral cell types. The synchronization signals (Zeitgebers) can be controlled more or less directly by the SCN. In mice and rats, feeding-fasting rhythms, which are driven by the SCN through rest-activity cycles, are the most potent Zeitgebers for the circadian oscillators of peripheral organs. Signaling through the glucocorticoid receptor and the serum response factor also participate in the phase entrainment of peripheral clocks, and these two pathways are controlled by the SCN independently of feeding-fasting rhythms. Body temperature rhythms, governed by the SCN directly and indirectly through rest-activity cycles, are perhaps the most surprising cues for peripheral oscillators. Although the molecular makeup of circadian oscillators is nearly identical in all cells, these oscillators are used for different purposes in the SCN and in peripheral organs.

Application of distributed lighting control architecture in dementia-friendly smart homes

Dementia is a growing problem in societies with aging populations, not only for patients, but also for family members and for the society in terms of the associated costs of providing health care. Helping patients to maintain a degree of independence in their home environment while ensuring their safeties is considered as a positive step forward for addressing individual needs of dementia patients. A common symptom for dementia patients including those with Alzheimer's Disease and Related Dementia (ADRD) is sleep disturbance, patients being awake at night and asleep during the day. One of the problems with night time sleep disturbance in dementia patients is the possible accidental falls of patients in the dark environment. An issue associated with un-hourly sleeping behavior in these patients is the lighting condition of their surroundings. Clinical studies indicate that appropriate level of lightning can help to restore the rest-activity cycles of ADRD patients. This study tackles this problem by generating machine learning solutions for controlling the lighting conditions of multiple rooms in the house in different hours based on patterns of behaviors generated for the patient. Several neural network oriented classification methods are investigated and their feasibilities are assessed with a collection of synthetic data capturing two conditions of balanced and unbalanced inter-class samples. The classifiers are utilized within two centric and distributed lighting control architectures. The results indicate the feasibility of the distributed architecture in achieving a high level of classification performance resulting in adequate control over lighting conditions of the house in various time periods.

Shift work and endocrine disorders.

The objective of this review was to investigate the impact of shift and night work on metabolic processes and the role of alterations in the sleep-wake cycle and feeding times and environmental changes in the occurrence of metabolic disorders. The literature review was performed by searching three electronic databases for relevant studies published in the last 10 years. The methodological quality of each study was assessed, and best-evidence synthesis was applied to draw conclusions. The literature has shown changes in concentrations of melatonin, cortisol, ghrelin, and leptin among shift workers. Melatonin has been implicated for its role in the synthesis and action of insulin. The action of this hormone also regulates the expression of transporter glucose type 4 or triggers phosphorylation of the insulin receptor. Therefore, a reduction in melatonin can be associated with an increase in insulin resistance and a propensity for the development of diabetes. Moreover, shift work can negatively affect sleep and contribute to sedentarism, unhealthy eating habits, and stress. Recent studies on metabolic processes have increasingly revealed their complexity. Physiological changes induced in workers who invert their activity-rest cycle to fulfill work hours include disruptions in metabolic processes.

Commentary on 'Antenatal cardiotocogram quality and interpretation using computers'.

Commentary on 'Antenatal cardiotocogram quality and interpretation using computers'.

Circadian rhythm sleep disorders in psychiatric diseases

Circadian rhythm sleep disorders are prevalent among psychiatric patients. This is most probable due to a close relationship between functional disturbances of the internal clock, sleep regulation and mental health. Mechanisms on molecular level of the circadian clock and neurotransmitter signalling are involved in the development of both disorders. Moreover, circadian disorders and psychiatric diseases favour each other by accessory symptoms such as stress or social isolation. Actimetry to objectively quantify the rest-activity cycle and salivary melatonin profiles as marker for the circadian phase help to diagnose circadian rhythm sleep disorders in psychiatric patients. Chronotherapeutics such as bright light therapy, dark therapy, melatonin administration, and wake therapy are used to synchronise and consolidate circadian rhythms and help in the treatment of depression and other psychiatric disorders, but are still neglected in medicine. More molecular to behavioural research is needed for the understanding of the development of circadian disorders and their relationship to psychiatric illnesses. This will help to boost the awareness and treatment of circadian rhythm sleep disorders in psychiatry.

Reduced brown adipose tissue thermogenesis during environmental interactions in transgenic rats with ataxin-3-mediated ablation of hypothalamic orexin neurons

Thermogenesis in brown adipose tissue (BAT) contributes to substantial increases in body temperature evoked by threatening or emotional stimuli. BAT thermogenesis also contributes to increases in body temperature that occur during active phases of the basic rest-activity cycle (BRAC), as part of normal daily life. Hypothalamic orexin-synthesizing neurons influence many physiological and behavioral variables, including BAT and body temperature. In conscious unrestrained animals maintained for 3 days in a quiet environment (24-26°C) with ad libitum food and water, we compared temperatures in transgenic rats with ablation of orexin neurons induced by expression of ataxin-3 (Orx_Ab) with wild-type (WT) rats. Both baseline BAT temperature and baseline body temperature, measured at the onset of BRAC episodes, were similar in Orx_Ab and WT rats. The time interval between BRAC episodes was also similar in the two groups. However, the initial slopes and amplitudes of BRAC-related increases in BAT and body temperature were reduced in Orx_Ab rats. Similarly, the initial slopes and amplitudes of the increases in BAT temperatures induced by sudden exposure to an intruder rat (freely moving or confined to a small cage) or by sudden exposure to live cockroaches were reduced in resident Orx_Ab rats. Constriction of the tail artery induced by salient alerting stimuli was also reduced in Orx_Ab rats. Our results suggest that orexin-synthesizing neurons contribute to the intensity with which rats interact with the external environment, both when the interaction is "spontaneous" and when the interaction is provoked by threatening or salient environmental events.

Chronic artificial blue-enriched white light is an effective countermeasure to delayed circadian phase and neurobehavioral decrements.

Studies in Polar Base stations, where personnel have no access to sunlight during winter, have reported circadian misalignment, free-running of the sleep-wake rhythm, and sleep problems. Here we tested light as a countermeasure to circadian misalignment in personnel of the Concordia Polar Base station during the polar winter. We hypothesized that entrainment of the circadian pacemaker to a 24-h light-dark schedule would not occur in all crew members (n = 10) exposed to 100–300 lux of standard fluorescent white (SW) light during the daytime, and that chronic non-time restricted daytime exposure to melanopsin-optimized blue-enriched white (BE) light would establish an a stable circadian phase, in participants, together with increased cognitive performance and mood levels. The lighting schedule consisted of an alternation between SW lighting (2 weeks), followed by a BE lighting (2 weeks) for a total of 9 weeks. Rest-activity cycles assessed by actigraphy showed a stable rest-activity pattern under both SW and BE light. No difference was found between light conditions on the intra-daily stability, variability and amplitude of activity, as assessed by non-parametric circadian analysis. As hypothesized, a significant delay of about 30 minutes in the onset of melatonin secretion occurred with SW, but not with BE light. BE light significantly enhanced well being and alertness compared to SW light. We propose that the superior efficacy of blue-enriched white light versus standard white light involves melanopsin-based mechanisms in the activation of the non-visual functions studied, and that their responses do not dampen with time (over 9-weeks). This work could lead to practical applications of light exposure in working environment where background light intensity is chronically low to moderate (polar base stations, power plants, space missions, etc.), and may help design lighting strategies to maintain health, productivity, and personnel safety.

The Tau Mutation of Casein Kinase 1ϵ Sets the Period of the Mammalian Pacemaker via Regulation of Period1 or Period2 Clock Proteins

The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian pacemaker in mammals, coordinating daily metabolic and physiological rhythms with the cycle of sleep and wakefulness. SCN neurons define circadian time via an auto-regulatory feedback loop in which the activation of Period (Per) and Cryptochrome genes is periodically suppressed by their own protein products. Casein kinase 1 (CK1) enzymes have a critical role in circadian pacemaking because they phosphorylate PER proteins and thereby direct their proteasomal degradation. In human pedigrees, individual mutations in either hCK1 or hPER2 lead to advanced sleep phase disorders, whereas in rodents, the Tau mutation of CK1 epsilon (CK1ϵTau) accelerates rest-activity cycles and shortens the period of the SCN molecular pacemaker. Biochemical analyses of recombinant PER proteins in cultured cells and endogenous proteins in peripheral tissues have identified PER1 and PER2, but not PER3, as direct substrates of CK1ϵ. The purpose of this study, therefore, was to determine the relative contributions of endogenous PER proteins to the period-accelerating effects of CK1ϵTau, both in vivo and in vitro. CK1ϵTau mice were mated onto Per1-, Per2-, and Per1-Per2 (Per1/2) double-null backgrounds, in all cases carrying the Per1-luciferase bioluminescent circadian reporter gene. Mice lacking both PER1 and PER2 were behaviorally arrhythmic, confirming the inadequacy of PER3 as a circadian factor. Individual loss of either PER1 or PER2 had no significant effect on the circadian period or quality of wheel-running behavior, and CK1ϵTau accelerated behavioral rhythms in both Per1- and Per2-null mice. CK1ϵTau also accelerated in vitro molecular pacemaking in SCN lacking either PER1 or PER2, with a greater effect in PER2-dependent (i.e., Per1-null) SCN than in PER1-dependent slices. In double-null slices, some SCN were arrhythmic, whereas others exhibited transient rhythms, which trended nonsignificantly toward a shorter period. Both short-period and long-period rhythms could be identified in individual SCN neurons imaged by charge-coupled device camera. CK1ϵTau had no effect, however, on SCN-level or individual neuronal rhythms in the absence of PER1 and PER2. Thus, the CK1ϵTau allele has divergent actions, acting via both endogenous PER1 and PER2, but not PER3 protein, to mediate its circadian actions in vivo. Moreover, PER-independent cellular oscillations may contribute to pacemaking, but they are unstable and imprecise, and are not affected by the Tau mutation.

Genetic polymorphisms of DAT1 and COMT differentially associate with actigraphy-derived sleep–wake cycles in young adults

Accumulating evidence suggests that dopamine plays a key role in sleep–wake regulation. Cerebral dopamine levels are regulated primarily by the dopamine transporter (DAT) in the striatum and by catechol-O-methyl-transferase (COMT) in the prefrontal cortex. We hypothesized that the variable-number-tandem-repeat (VNTR) polymorphism in the 3′-untranslated region of the gene encoding DAT (DAT1, SLC6A3; rs28363170) and the Val158Met polymorphism of COMT (rs4680) differently affect actigraphy-derived rest-activity cycles and sleep estimates in healthy adults (65 men; 45 women; age range: 19–35 years). Daytime sleepiness, continuous rest-actigraphy and sleep diary data during roughly 4-weeks were analyzed. Nine-repeat (9R) allele carriers of DAT1 (n = 48) more often reported elevated sleepiness (Epworth sleepiness score ≥10) than 10-repeat (10R) allele homozygotes (n = 62, p < 0.02). Moreover, male 9R allele carriers showed higher wrist activity, whereas this difference was not present in women (“DAT1 genotype” × “gender” interaction: p < 0.005). Rest-activity patterns did not differ among COMT genotypes. Nevertheless, a significant “COMT genotype” × “type of day” (workdays vs. rest days) interaction for sleep duration was observed (p = 0.04). The Val/Val (n = 36) and Met/Met (n = 24) homozygotes habitually prolonged sleep on rest days compared to workdays by more than 30 min, while Val/Met heterozygotes (n = 50) did not significantly extend their sleep (mean difference: 7 min). Moreover, whereas the proportion of women among the genotype groups did not differ, COMT genotype affected body-mass-index (BMI), such that Val/Met individuals had lower BMI than the homozygous genotypes (p < 0.04). While awaiting independent replication and confirmation, our data support an association of genetically-determined differences in cerebral dopaminergic neurotransmission with daytime sleepiness and individual rest-activity profiles, as well as other sleep-associated health characteristics such as the regulation of BMI. The differential associations of DAT1 and COMT polymorphisms may reflect the distinct local expression of the encoded proteins in the brain.

Social Modulation of Circadian Synchronization and Temporal Perception in Complete Isolation

Social Modulation of Circadian Synchronization and Temporal Perception in Complete Isolation

Time- and Behavioral State-Dependent Changes in Posterior Hypothalamic GABAA Receptors Contribute to the Regulation of Sleep

Sleep-wake behavior is regulated by a circadian rhythm, homeostatically and by additional mechanisms that determine the timing of slow-wave sleep and rapid eye movement sleep (REMS) episodes. The posterior hypothalamus coordinates the neural and humoral signals with the rest-activity cycle. It contains wake-active neurons, and is a site where stimulation of inhibitory GABAA receptors promotes sleep, whereas their antagonism enhances wakefulness. We explored whether GABAergic mechanisms present in the posterior hypothalamus contribute to the homeostatic and other aspects of sleep-wake regulation. Using micropunches of tissue extracted from either the perifornical (PF) or dorsomedial (DM) regions of the posterior hypothalamus of rats, we determined that mRNA levels for selected subunits of GABAA receptors (β1, β3 and ε) were higher at the end of the active period or following sleep deprivation, when the need for sleep is high, than after several hours of sleep, when sleep need is partially fulfilled. Such a pattern was present in the PF region only, and was consistent with changes in β1 subunit and GABA synthesizing enzyme (GAD) protein levels. In contrast, in the DM region, the levels of GABAA receptor subunit mRNAs and proteins (α1, α2, β1) and GAD varied with circadian time, but were not responsive to sleep deprivation. Separate experiments with sleep-wake monitoring and local perfusion of the PF region with the GABAA receptor antagonist bicuculline revealed that the antagonist had a weaker sleep-reducing effect when sleep need was enhanced by sleep deprivation and that the increased amount of REMS characteristic of the late sleep period was dependent on endogenous GABAergic inhibition. These results support the concept that a varying magnitude of GABAergic inhibition exerted within the PF region contributes to the homeostatic regulation of sleep and shapes its temporal pattern, whereas GABAergic mechanisms in the DM region contribute to circadian regulation.

Regulation of circadian rhythms in mammals by behavioral arousal.

Circadian rhythms in most mammals are synchronized to local time by phase and period resetting actions of daily light-dark cycles on a retino-recipient, light-entrainable circadian pacemaker, the suprachiasmatic nucleus (SCN). The SCN receives input from other brain regions, some of which mediate the phase and period resetting actions of behavioral arousal on circadian rhythms. We review historical milestones in the discovery of so-called "nonphotic" circadian clock resetting induced by environmentally stimulated arousal, or by feedback from clock-controlled rest-activity cycles. Topics include species generality, interactions between concurrent or successive photic and nonphotic inputs to the circadian clock, neural pathways, neurotransmitters, and clock cell responses that mediate resetting by behavioral arousal. The role of behavioral inputs to the circadian clock in determining the phase of entrainment to local time in natural environments is not well understood. Nonetheless, nonphotic effects are of sufficient magnitude to raise issues for the design of experiments in behavioral neuroscience (any procedure that is sufficiently arousing may alter the timing of circadian clocks that regulate dependent variables of primary interest). Nonphotic inputs to the clock may be exploited in strategies to reset or strengthen circadian rhythms in humans.