Circadian Pacemaker Research Articles

Circadian misalignment increases mood vulnerability in simulated shift work

Night shift work can associate with an increased risk for depression. As night workers experience a ‘misalignment’ between their circadian system and daily sleep–wake behaviors, with negative health consequences, we investigated whether exposure to circadian misalignment underpins mood vulnerability in simulated shift work. We performed randomized within-subject crossover laboratory studies in non-shift workers and shift workers. Simulated night shifts were used to induce a misalignment between the endogenous circadian pacemaker and sleep/wake cycles (circadian misalignment), while environmental conditions and food intake were controlled. Circadian misalignment adversely impacted emotional state, such that mood and well-being levels were significantly decreased throughout 4 days of continuous exposure to circadian misalignment in non-shift workers, as compared to when they were under circadian alignment (interaction of “circadian alignment condition” vs. “day”, mood: p < 0.001; well-being: p < 0.001; adjusted p-values). Similarly, in shift workers, mood and well-being levels were significantly reduced throughout days of misalignment, as compared to circadian alignment (interaction of “circadian alignment condition” vs. “day”, mood: p = 0.002; well-being: p = 0.002; adjusted p-values). Our findings indicate that circadian misalignment is an important biological component for mood vulnerability, and that individuals who engage in shift work are susceptible to its deleterious mood effects.

Light Has Diverse Spatiotemporal Molecular Changes in the Mouse Suprachiasmatic Nucleus.

To be physiologically relevant, the period of the central circadian pacemaker, located in the suprachiasmatic nucleus (SCN), has to match the solar day in a process known as circadian photoentrainment. However, little is known about the spatiotemporal molecular changes that occur in the SCN in response to light. In this study, we sought to systematically characterize the circadian and light effects on activity-dependent markers of transcriptional (cFos), translational (pS6), and epigenetic (pH3) activities in the mouse SCN. To investigate circadian versus light influences on these molecular responses, we harvested brains from adult wild-type mice in darkness at different circadian times (CT) or from mice exposed to a 15-min light pulse at the middle of the subjective day (CT6, no phase shifts), early subjective night (CT14, large phase delays), or late subjective night (CT22, small phase advances). We found that cFos and pS6 exhibited rhythmic circadian expression in the SCN with distinct spatial rhythms, whereas pH3 expression was undetectable at all circadian phases. cFos rhythms were largely limited to the SCN shell, whereas pS6 rhythms encompassed the entire SCN. pH3, pS6, and cFos showed gating in response to light; however, we were surprised to find that the expression levels of these markers were not higher at phases when larger phase shifts are observed behaviorally (CT14 versus CT22). We then used animals lacking melanopsin (melanopsin knockout [MKO]), which show deficits in phase delays, to further investigate whether changes in these molecular markers correspond to behavioral phase shifts. Surprisingly, only pS6 showed deficits in MKOs at CT14. Therefore, our previous understanding of the molecular pathways that lead to circadian photoentrainment needs to be revised.

Parameter Estimation in a Model of the Human Circadian Pacemaker Using a Particle Filter.

In the near future, real-time estimation of peoples unique, precise circadian clock state has the potential to improve the efficacy of medical treatments and improve human performance on a broad scale. Human-centric lighting can bring circadian-rhythm support using biodynamic lighting solutions that sync light with the time of day. We investigate a method to improve the tracking of individual's circadian processes. In literature, the human circadian physiology has been mathematically modeled using ordinary differential equations, the state of which can be tracked via the signal processing concept of a Particle Filter. We show that substantial improvements can be made if the estimator not only tracks state variables, such as the phase and amplitude of the circadian pacemaker, but also fits specific model parameters to the individual. In particular, we optimize model parameter τx, which reflects the intrinsic period of the circadian pacemaker ( τ). We show that both state and model parameters can be estimated based on minimally-invasive light exposure measurements and sleep-wake state observations. We also quantify the effect of inaccuracies in sensing. We demonstrate improved performance by estimating τx for every individual, both with artificially created and human subject data. Prediction accuracy improves with every newly available observation. The estimated τx-s correlate well with the subjects' chronotypes, in a similar way as τ correlates. Our results show that individualizing the estimation of model parameters can improve circadian state estimation accuracy. These findings underscore the potential improvements in personalized models over one-size fits all approaches.

Circadian Regulation of GluA2 mRNA Processing in the Rat Suprachiasmatic Nucleus and Other Brain Structures.

The mammalian circadian system consists of a major circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks in the body, including brain structures. The SCN depends on glutamatergic neurotransmission for transmitting signals from the retina, and it exhibits spontaneous 24-h rhythmicity in neural activity. The aim of this work was to evaluate the degree and circadian rhythmicity of AMPA receptor GluA2 subunit R/G editing and alternative flip/flop splicing in the SCN and other brain structures in Wistar rats. Our data show that the circadian rhythmicity in the SCN's GluA2 mRNA level was highest at dawn, while the circadian rhythm in R/G editing peaked at CT10 and the rhythmic flip varied with the acrophase at the late subjective night. The circadian rhythmicity was confirmed for R/G editing and splicing in the CA3 hippocampal area, and rhythmic variation of the flip isoform was also measured in the olfactory bulbs and cerebellum. The correlations between the R/G editing and alternative flip/flop splicing revealed a structure-dependent direction. In the hippocampus, the edited (G)-form level was positively correlated with the flip variant abundance, in accord with published data; by contrast, in the SCN, the flip variant was in associated more with the unedited (R) form. The edited (G) form and flop isoform also predominated in the retina and cerebellum.

The genetic basis of diurnal preference in Drosophila melanogaster

BackgroundMost animals restrict their activity to a specific part of the day, being diurnal, nocturnal or crepuscular. The genetic basis underlying diurnal preference is largely unknown. Under laboratory conditions, Drosophila melanogaster is crepuscular, showing a bi-modal activity profile. However, a survey of strains derived from wild populations indicated that high variability among individuals exists, including flies that are nocturnal.ResultsUsing a highly diverse population, we performed an artificial selection experiment, selecting flies with extreme diurnal or nocturnal preference. After 10 generations, we obtained highly diurnal and nocturnal strains. We used whole-genome expression analysis to identify differentially expressed genes in diurnal, nocturnal and crepuscular (control) flies. Other than one circadian clock gene (pdp1), most differentially expressed genes were associated with either clock output (pdf, to) or input (Rh3, Rh2, msn). This finding was congruent with behavioural experiments indicating that both light masking and the circadian pacemaker are involved in driving nocturnality.ConclusionsOur study demonstrates that genetic variation segregating in wild populations contributes to substantial variation in diurnal preference. We identified candidate genes associated with diurnality/nocturnality, while data emerging from our expression analysis and behavioural experiments suggest that both clock and clock-independent pathways are involved in shaping diurnal preference. The diurnal and nocturnal selection strains provide us with a unique opportunity to understand the genetic architecture of diurnal preference.

Brief light exposure at dawn and dusk can encode day-length in the neuronal network of the mammalian circadian pacemaker.

The central circadian pacemaker in mammals, the suprachiasmatic nucleus (SCN), is important for daily as well as seasonal rhythms. The SCN encodes seasonal changes in day length by adjusting phase distribution among oscillating neurons thereby shaping the output signal used for adaptation of physiology and behavior. It is well-established that brief light exposure at the beginning and end of the day, also referred to as "skeleton" light pulses, are sufficient to evoke the seasonal behavioral phenotype. However, the effect of skeleton light exposure on SCN network reorganization remains unknown. Therefore, we exposed mice to brief morning and evening light pulses that mark the time of dawn and dusk in a short winter- or a long summer day. Single-cell PER2::LUC recordings, electrophysiological recordings of SCN activity, and measurements of GABA response polarity revealed that skeleton light-regimes affected the SCN network to the same degree as full photoperiod. These results indicate the powerful, yet potentially harmful effects of even relatively short light exposures during the evening or night for nocturnal animals.

Transition of Neural Activity From the Chaotic Bipolar-Disorder State to the Periodic Healthy State Using External Feedback Signals.

Chronotherapy is a treatment for mood disorders, including major depressive disorder, mania, and bipolar disorder (BD). Neurotransmitters associated with the pathology of mood disorders exhibit circadian rhythms. A functional deficit in the neural circuits related to mood disorders disturbs the circadian rhythm; chronotherapy is an intervention that helps resynchronize the patient's biological clock with the periodic daily cycle, leading to amelioration of symptoms. In previous reports, Hadaeghi et al. proposed a non-linear dynamic model composed of the frontal and sensory cortical neural networks and the hypothalamus to explain the relationship between deficits in neural function in the frontal cortex and the disturbed circadian rhythm/mood transitions in BD (hereinafter referred to as the Hadaeghi model). In this model, neural activity in the frontal and sensory lobes exhibits periodic behavior in the healthy state; while in BD, this neural activity is in a state of chaos-chaos intermittency; this temporal departure from the healthy periodic state disturbs the circadian pacemaker in the hypothalamus. In this study, we propose an intervention based on a feedback method called the “reduced region of orbit” (RRO) method to facilitate the transition of the disturbed frontal cortical neural activity underlying BD to healthy periodic activity. Our simulation was based on the Hadaeghi model. We used an RRO feedback signal based on the return-map structure of the simulated frontal and sensory lobes to induce synchronization with a relatively weak periodic signal corresponding to the healthy condition by applying feedback of appropriate strength. The RRO feedback signal induces chaotic resonance, which facilitates the transition to healthy, periodic frontal neural activity, although this synchronization is restricted to a relatively low frequency of the periodic input signal. Additionally, applying an appropriate strength of the RRO feedback signal lowered the amplitude of the periodic input signal required to induce a synchronous state compared with the periodic signal applied alone. In conclusion, through a chaotic-resonance effect induced by the RRO feedback method, the state of the disturbed frontal neural activity characteristic of BD was transformed into a state close to healthy periodic activity by relatively weak periodic perturbations. Thus, RRO feedback-modulated chronotherapy might be an innovative new type of minimally invasive chronotherapy.

CAMP response element induces Per1 in vivo

Light is an important cue for resetting the circadian clock. In mammals, light signals are thought to be transmitted to the cAMP response element (CRE) via a binding protein (CREB) to induce the expression of Per1 and Per2 genes in the mammalian circadian pacemaker, the suprachiasmatic nuclei (SCN). Several in vitro studies have suggested candidate CRE sites that contribute to the Per1 and Per2 induction by light, resulting in a phase shift of the circadian rhythm. However, it remains unclear whether the CREs are responsible for the light-induced Per1/2 induction. To address this question, we generated CRE-deleted mice in the Per1 and Per2 promoter regions. Deletion of a cAMP-responsive CRE in the Per1 promoter blunted light-induced Per1 expression in the SCN at night, while deletion of an ATF4 (CREB-2)-associated CRE in the Per2 promoter had no effect on its expression. These results suggested that the CRE in the Per1 promoter works for light induction but not CRE in the Per2 promoter. Behavioral rhythms observed under some light conditions were not affected by the CRE-deletion in Per1 promoter, suggesting that the attenuated Per1 induction did not affect the entrainment in some light conditions.

Zebrafish Circadian Clock Entrainment and the Importance of Broad Spectral Light Sensitivity.

One of the key defining features of an endogenous circadian clock is that it can be entrained or set to local time. Though a number of cues can perform this role, light is the predominant environmental signal that acts to entrain circadian pacemakers in most species. For the past 20 years, a great deal of work has been performed on the light input pathway in mammals and the role of intrinsically photosensitive retinal ganglion cells (ipRGCs)/melanopsin in detecting and sending light information to the suprachiasmatic nucleus (SCN). In teleost fishes, reptiles and birds, the biology of light sensitivity is more complicated as cells and tissues can be directly light responsive. Non-visual light signalling was described many years ago in the context of seasonal, photoperiodic responses in birds and lizards. In the case of teleosts, in particular the zebrafish model system, not only do peripheral tissues have a circadian pacemaker, but possess clear, direct light sensitivity. A surprisingly wide number of opsin photopigments have been described within these tissues, which may underpin this fundamental ability to respond to light, though no specific functional link for any given opsin yet exists. In this study, we show that zebrafish cells show wide spectral sensitivities, as well as express a number of opsin photopigments – several of which are under direct clock control. Furthermore, we also show that light outside the visual range, both ultraviolet and infrared light, can induce clock genes in zebrafish cells. These same wavelengths can phase shift the clock, except infrared light, which generates no shift even though genes such as per2 and cry1a are induced.

Personalized Office Lighting for Circadian Health and Improved Sleep.

In modern society, the average person spends more than 90% of their time indoors. However, despite the growing scientific understanding of the impact of light on biological mechanisms, the existing light in the built environment is designed predominantly to meet visual performance requirements only. Lighting can also be exploited as a means to improve occupant health and well-being through the circadian functions that regulate sleep, mood, and alertness. The benefits of well-lit spaces map across other regularly occupied building types, such as residences and schools, as well as patient rooms in healthcare and assisted-living facilities. Presently, Human Centric Lighting is being offered based on generic insights on population average experiences. In this paper, we suggest a personalized bio-adaptive office lighting system, controlled to emit a lighting recipe tailored to the individual employee. We introduce a new mathematical optimization for lighting schedules that align the 24-h circadian cycle. Our algorithm estimates and optimizes parameters in experimentally validated models of the human circadian pacemaker. Moreover, it constrains deviations from the light levels desired and needed to perform daily activities. We further translate these into general principles for circadian lighting. We use experimentally validated models of the human circadian pacemaker to introduce a new algorithm to mathematically optimize lighting schedules to achieve circadian alignment to the 24-h cycle, with constrained deviations from the light levels desired for daily activities. Our suggested optimization algorithm was able to translate our findings into general principles for circadian lighting. In particular, our simulation results reveal: (1) how energy constrains drive the shape of optimal lighting profiles by dimming the light levels in the time window that light is less biologically effective; (2) how inter-individual variations in the characteristic internal duration of the day shift the timing of optimal lighting exposure; (3) how user habits and, in particular, late-evening light exposure result in differentiation in late afternoon office lighting.

Anatomical and ultrastructural analysis of the posterior optic tubercle in the locust Schistocerca gregaria

Locusts, like other insects, partly rely on a sun compass mechanism for spatial orientation during seasonal migrations. To serve as a useful guiding cue throughout the day, however, the sun's apparent movement has to be accounted for. In locusts, a neural pathway from the accessory medulla, the circadian pacemaker, via the posterior optic tubercle, to the protocerebral bridge, part of the internal sky compass, has been proposed to mediate the required time compensation. Toward a better understanding of neural connectivities within the posterior optic tubercle, we investigated this neuropil using light and electron microscopy. Based on vesicle content, four types of synaptic profile were distinguished within the posterior optic tubercle. Immunogold labeling showed that pigment-dispersing hormone immunoreactive neurons from the accessory medulla, containing large dense-core vesicles, have presynaptic terminals in the posterior optic tubercle. Ultrastructural examination of two Neurobiotin-injected tangential neurons of the protocerebral bridge revealed that these neurons are postsynaptic in the posterior optic tubercle. Our data, therefore, support a role of the posterior optic tubercles in mediating circadian input to the insect sky compass.

Chronobiology: Human circadian pacemaker and circadian rhythms

Chronobiology: Human circadian pacemaker and circadian rhythms

Robust light\u2013dark patterns and reduced amyloid load in an Alzheimer\u2019s disease transgenic mouse model

Circadian disruption resulting from exposure to irregular light–dark patterns and sleep deprivation has been associated with beta amyloid peptide (Aβ) aggregation, which is a major event in Alzheimer’s disease (AD) pathology. We exposed 5XFAD mice and littermate controls to dim-light vs. bright-light photophases to investigate the effects of altering photophase strength on AD-associated differences in cortical Aβ42 levels, wheel-running activity, and circadian free-running period (tauDD). We found that increasing light levels significantly reduced cortical Aβ42 accumulation and activity levels during the light phase of the light:dark cycle, the latter being consistent with decreased sleep fragmentation and increased sleep duration for mice exposed to the more robust light–dark pattern. No significant changes were observed for tauDD. Our results are consistent with circadian pacemaker period being relatively unaffected by Aβ pathology in AD, and with reductions in cortical Aβ loads in AD through tailored lighting interventions.

Gap Junction Protein INNEXIN2 Modulates the Period of Activity-Rest Rhythms in &lt;i&gt;Drosophila Melanogaster&lt;/i&gt;

The circadian neuronal circuit of Drosophila melanogaster is made up of about 150 neurons, distributed bilaterally and distinguished into 7 clusters. Multiple lines of evidence suggest that coherent rhythms in behaviour are brought about when these clusters function as a network. Although chemical modes of communication amongst circadian neurons have been well-studied, there has been no report of communication via electrical synapses made up of gap junctions. Here, we report for the first time that gap junction proteins - Innexins play crucial roles in determining the period of free-running activity rhythms in flies. Our experiments reveal the presence of gap junction protein INNEXIN2 in the ventral lateral neurons. RNA-interference based knockdown of its expression in circadian pacemakers slows down the speed of locomotor activity rhythm. Concomitantly, we find alterations in the oscillation of a core-clock protein PERIOD and in the output molecule Pigment Dispersing Factor in the circadian pacemaker neuron network.

Nitric oxide mediates neuro-glial interaction that shapes Drosophila circadian behavior.

Drosophila circadian behavior relies on the network of heterogeneous groups of clock neurons. Short- and long-range signaling within the pacemaker circuit coordinates molecular and neural rhythms of clock neurons to generate coherent behavioral output. The neurochemistry of circadian behavior is complex and remains incompletely understood. Here we demonstrate that the gaseous messenger nitric oxide (NO) is a signaling molecule linking circadian pacemaker to rhythmic locomotor activity. We show that mutants lacking nitric oxide synthase (NOS) have behavioral arrhythmia in constant darkness, although molecular clocks in the main pacemaker neurons are unaffected. Behavioral phenotypes of mutants are due in part to the malformation of neurites of the main pacemaker neurons, s-LNvs. Using cell-type selective and stage-specific gain- and loss-of-function of NOS, we also demonstrate that NO secreted from diverse cellular clusters affect behavioral rhythms. Furthermore, we identify the perineurial glia, one of the two glial subtypes that form the blood-brain barrier, as the major source of NO that regulates circadian locomotor output. These results reveal for the first time the critical role of NO signaling in the Drosophila circadian system and highlight the importance of neuro-glial interaction in the neural circuit output.

Prenatal exposure to lipopolysaccharide induces changes in the circadian clock in the SCN and AA-NAT activity in the pineal gland

The mammalian circadian pacemaker in the suprachiasmatic nucleus (SCN) regulates behavioral and physiological processes in a 24-h cycle. During its development, the SCN can be sensitive to external stimuli which may change the circadian phenotypes in adulthood. Here, we investigated the effects of prenatal exposure to endotoxin lipopolysaccharide (LPS) on the developing rhythms in expression of Per1, Per2, Nr1d1 and Rasd1 along the rostrocaudal axis of the SCN, and on the rhythm of the rate-limiting enzyme in melatonin synthesis, pineal alkylamine N-acetyltransferase (AA-NAT). The prenatal LPS treatment induced anxiety-like behavior in adulthood as shown before and affected the rhythmicity of clock genes in the SCN. The major effect was observed for Nr1d1 expression; the least affected gene was Per2. The Nr1d1 in the LPS-treated group was arrhythmic at postnatal day 3, but showed significantly higher amplitude at postnatal day 20 at all SCN parts, similarly to the AA-NAT activity in pineal glands, thus suggesting adaptive flexibility of the developing SCN to immune challenges in early development.

Fasting blood triglycerides vary with circadian phase in both young and older people.

Daily rhythms in several physiological processes are important for cardiometabolic health. The lipid panel is used clinically to assess cardiovascular disease risk, but previous attempts to demonstrate circadian variation in lipids have failed to uncouple the endogenous circadian rhythm from the effects of meals and wake duration. Changes in basal lipid levels and dampening of circadian rhythms have been reported with aging, but it is unknown whether aging is also associated with changes in the rhythmic variation of lipids. We measured fasting lipid panels (triglycerides, total cholesterol, high‐density lipoprotein, and low‐density lipoprotein) in blood at wake time in 21 healthy adults using a specialized laboratory protocol that uncouples sleep–wake and activity‐related effects from the endogenous circadian rhythm. Young and older adults exhibited endogenous circadian variations in fasting triglycerides, with both groups peaking in the early biological morning. Young adults also exhibited significant circadian rhythmicity in total cholesterol and low‐density lipoprotein, while older adults did not exhibit circadian rhythmicity in any other lipids. These results reveal that triglyceride metabolism may be regulated by the central circadian pacemaker. Moreover, our findings may have clinical implications in assessing cardiovascular risk in shift workers and younger adults, since routine measurement of morning/fasting lipids may not fully and reliably assess triglyceride‐ and other lipid‐related biomarkers of cardiovascular disease risk in these groups.

Analysis of Pigment-Dispersing Factor Neuropeptides and Their Receptor in a Velvet Worm.

Pigment-dispersing factor neuropeptides (PDFs) occur in a wide range of protostomes including ecdysozoans (= molting animals) and lophotrochozoans (mollusks, annelids, flatworms, and allies). Studies in insects revealed that PDFs play a role as coupling factors of circadian pacemaker cells, thereby controlling rest-activity rhythms. While the last common ancestor of protostomes most likely possessed only one pdf gene, two pdf homologs, pdf-I and pdf-II, might have been present in the last common ancestors of Ecdysozoa and Panarthropoda (Onychophora + Tardigrada + Arthropoda). One of these homologs, however, was subsequently lost in the tardigrade and arthropod lineages followed by independent duplications of pdf-I in tardigrades and decapod crustaceans. Due to the ancestral set of two pdf genes, the study of PDFs and their receptor (PDFR) in Onychophora might reveal the ancient organization and function of the PDF/PDFR system in panarthropods. Therefore, we deorphanized the PDF receptor and generated specific antibodies to localize the two PDF peptides and their receptor in the onychophoran Euperipatoides rowelli. We further conducted bioluminescence resonance energy transfer (BRET) experiments on cultured human cells (HEK293T) using an Epac-based sensor (Epac-L) to examine cAMP responses in transfected cells and to reveal potential differences in the interaction of PDF-I and PDF-II with PDFR from E. rowelli. These data show that PDF-II has a tenfold higher potency than PDF-I as an activating ligand. Double immunolabeling revealed that both peptides are co-expressed in E. rowelli but their respective levels of expression differ between specific cells: some neurons express the same amount of both peptides, while others exhibit higher levels of either PDF-I or PDF-II. The detection of the onychophoran PDF receptor in cells that additionally express the two PDF peptides suggests autoreception, whereas spatial separation of PDFR- and PDF-expressing cells supports hormonal release of PDF into the hemolymph. This suggests a dual role of PDF peptides—as hormones and as neurotransmitters/neuromodulators—in Onychophora.

Food anticipatory circadian rhythms in mice entrained to long or short day photoperiods

Food anticipatory activity (FAA) rhythms that emerge in nocturnal rodents fed once daily are mediated by food-entrainable circadian oscillators (FEOs) located outside of the suprachiasmatic nucleus (SCN), the site of a circadian pacemaker required for entrainment to daily light-dark (LD) cycles. Specification of the neural and molecular substrates of FEOs driving FAA is complicated by homeostatic, hedonic and environmental factors that can modulate expression of activity independent of circadian timing. Here, we examined the effect of photoperiod (duration of the daily light period) on FAA in mice fed during the last 4 h or middle 4 h of the light period for at least 5 weeks. Long photoperiods decrease SCN pacemaker amplitude, which may favor expression of FAA during the day, when the SCN normally opposes activity in nocturnal rodents. To test this prediction, in Experiment 1, mice housed with or without running discs were entrained to 24 h LD cycles with 8 h (L8) or 16 h (L16) photoperiods. When food was restricted to the last 4 h of the light period (late-day), mice housed with running discs showed more FAA in L16, whereas mice without running discs showed more FAA in L8. In Experiment 2, mice were entrained to L8 or L16 photoperiods, and the 4 h daily meal was centered in the light period (mid-day). FAA was decreased relative to late-day fed mice, but did not vary by photoperiod. In Experiment 3, mice with or without running discs were entrained to L12 or L18 photoperiods, with mealtime centered in the light period. FAA again did not differ between photoperiods. In constant dark (DD) prior to food restriction, the period (τ) of free-running rhythms was shorter in mice entrained to long days. This known after-effect of photoperiod on τ was absent in DD immediately following restricted feeding. The phase of LD entrainment, unmasked on the first day of DD with food ad-libitum, was significantly advanced in mice from the late-day feeding schedule, compared to mice from the mid-day schedules. These results indicate that FAA in mice does not vary systematically with photoperiod, possibly because daytime feeding schedules attenuate the effect of photoperiod on the mouse SCN pacemaker. FAA in the present study was more strongly influenced by running disc availability and by meal time within the light period, possibly due to effects on LD entrainment, which was phase advanced by late-day but not midday feeding.

Modified-release hydrocortisone for glucocorticoid deficiency

The central circadian pacemaker in the suprachiasmatic nucleus and interaction of clock genes with the hypothalamus pituitary adrenal axis are responsible for very distinct cortisol concentrations. Unphysiologically high doses of glucocorticoids that do not follow the circadian rhythm lead to increased rates of morbidity, mortality and reduced quality of life. Does aswitch to modified-release hydrocortisone in multimorbid elderly patients offer benefits compared to aconventional therapy regime? Evaluation, analysis and discussion of statistics, recent research results and expert advice. Overdosage and unphysiological timing of cortisol administration result in higher incidences of obesity, hypertension, hyperglycemia, coronary heart disease and cardiac events. Body weight, body mass index and HbA1c decline with Plenadren® (Shire Pharmaceuticals Ireland Limited, Dublin, Ireland) treatment compared to conventional therapy. CD16+ natural killer cells and natural killer cytotoxycity are reduced, and the incidence of respiratory-tract infections is increased, with conventional therapy compared to Plenadren®. Cortisol influences sleep pattern and sleep quality by its circadian secretion. Novel modified-release hydrocortisone preparations offer diverse benefits with regard to their effect on metabolism, cardiovascular risk, immunity and sleep, which might be beneficial in particular in multimorbid elderly.