Phase Advances In Circadian Rhythms Research Articles

Blue Wavelength Light Treatment for Improving Sleep in Patients with Post-Traumatic Stress Disorder

Traumatic live events comprise the etiology of post-traumatic stress disorder (PTSD). PTSD patients are known to face adverse impacts on their mental and physical health. Symptoms of concern relating to PTSD include heightened anxiety levels, intrusive memories, nightmares, and problems with sleeping. Disrupted sleep leads to exhausted brain function that impedes the daily activities of individuals and impacts their perceived quality of life. Therefore, researchers have sought to examine interventions that help improve sleep and circadian rhythms. Recently, blue-light therapy has been the target of clinical research to understand its role in alleviating PTSD symptoms. Results from clinical trials showed that patients receiving blue light showed significant reductions in daytime sleepiness and fatigue. Furthermore, these individuals showed faster reaction times and greater phase advances in circadian rhythms, leading to earlier sleep onset at night. As we work towards focusing our attention on addressing mental health issues, investigating the benefits of non-pharmacological interventions such as blue-light therapy can help improve the health outcomes of PTSD patients.

Cardiorespiratory Fitness Is Associated with Phase Advanced Circadian Rhythms in Healthy Adolescents

Cardiorespiratory Fitness Is Associated with Phase Advanced Circadian Rhythms in Healthy Adolescents

Melatonin, circadian rhythms and glaucoma: current perspective.

Melatonin, circadian rhythms and glaucoma: current perspective.

Modulation by adiponectin of circadian clock rhythmicity in model mice for metabolic syndrome

To assess the effect of adiponectin on the circadian rhythm disturbances associated with metabolic syndrome, we generated a KK/Ta mouse line expressing the human adiponectin transgene in the liver. Locomotor activity of control C57BL/6 mice was highest during the beginning of the dark period and low during the light period. Under constant darkness, the length of locomotor activity rhythm of control mice was slightly shorter than 24 h. In KK/Ta mice the peak of locomotor activity was blunted and significant activity was observed during the light period. Furthermore, KK/Ta mice showed shorter average period length of free-running locomotor activity rhythm when compared with control mice. However, the transgenic expression of adiponectin in the liver significantly altered the circadian rhythm of locomotor activity and the length of free-running rhythm of KK/Ta mice towards those of C57BL/6 mice. In the liver and skeletal muscles from control mice, mRNA levels of Arntl and Cry1 were increased during the dark period, whereas those of Dbp, Cry2, Per1 and Per2 were elevated during the light period. KK/Ta mice exhibited phase advances in circadian rhythms of Arntl, Dbp, Cry2 and Per2 in both tissues. The phase shifts of the circadian clock gene expression in the liver were attenuated in adiponectin-transgenic mice. These results suggest that adiponectin is a peripheral regulator of the circadian clocks in the brain and peripheral organs, and may be a novel target for the treatment of obesity-associated disorders of circadian rhythms.

Minimum Criteria for DNA Damage-Induced Phase Advances in Circadian Rhythms

Robust oscillatory behaviors are common features of circadian and cell cycle rhythms. These cyclic processes, however, behave distinctively in terms of their periods and phases in response to external influences such as light, temperature, nutrients, etc. Nevertheless, several links have been found between these two oscillators. Cell division cycles gated by the circadian clock have been observed since the late 1950s. On the other hand, ionizing radiation (IR) treatments cause cells to undergo a DNA damage response, which leads to phase shifts (mostly advances) in circadian rhythms. Circadian gating of the cell cycle can be attributed to the cell cycle inhibitor kinase Wee1 (which is regulated by the heterodimeric circadian clock transcription factor, BMAL1/CLK), and possibly in conjunction with other cell cycle components that are known to be regulated by the circadian clock (i.e., c-Myc and cyclin D1). It has also been shown that DNA damage-induced activation of the cell cycle regulator, Chk2, leads to phosphorylation and destruction of a circadian clock component (i.e., PER1 in Mus or FRQ in Neurospora crassa). However, the molecular mechanism underlying how DNA damage causes predominantly phase advances in the circadian clock remains unknown. In order to address this question, we employ mathematical modeling to simulate different phase response curves (PRCs) from either dexamethasone (Dex) or IR treatment experiments. Dex is known to synchronize circadian rhythms in cell culture and may generate both phase advances and delays. We observe unique phase responses with minimum delays of the circadian clock upon DNA damage when two criteria are met: (1) existence of an autocatalytic positive feedback mechanism in addition to the time-delayed negative feedback loop in the clock system and (2) Chk2-dependent phosphorylation and degradation of PERs that are not bound to BMAL1/CLK.

Serotonin 1A-mediated amplification of light-induced phase advances of circadian rhythms in the Syrian hamster: Post-light effects

Certain serotonergic compounds that have an agonist/antagonist activity at the 5-HT 1A receptor subtype are known to greatly potentiate the ability of light to advance the phase of circadian activity rhythms in hamsters. Typically, investigational compounds are injected 30 min to 1 h prior to a phase-advancing light pulse, and it is not known if these compounds are efficacious when injected after a short light pulse. In this study we injected the 5-HT 1A mixed agonist/antagonist BMY 7378 from 1 to 7 h after a short phase advancing light pulse at CT 19 in hamsters to assess the temporal window of efficacy of this compound. BMY 7378 effectively doubles the magnitude of light-induced phase advances in hamster circadian wheel running rhythms for 6 h after a light pulse administered at CT 19, and this effect abruptly ends at 7 h post-light. This demonstrates that the molecular events initiated by a light pulse at CT 19 responsible for initiating phase advances in circadian activity rhythms can be modulated for at least the next 6 h in the hamster. However, this effect found with BMY 7378 does not extend to all serotonergic compounds as the inhibitory activity of 8-OH-DPAT on light-induced phase advances is not apparent when injected just 3 h after a light pulse. Since BMY 7378 can elicit such major shifts in the timing of the circadian clock it should be useful as a tool to explore potential changes in gene expression that lead to phase shifts in circadian rhythms, now known to be susceptible to modification for 6 h after a phase-advancing light pulse.

Losing Sleep Over Cancer

Losing Sleep Over Cancer

Phase Resetting of the Mammalian Circadian Clock by DNA Damage

To anticipate the momentum of the day, most organisms have developed an internal clock that drives circadian rhythms in metabolism, physiology, and behavior [1]. Recent studies indicate that cell-cycle progression and DNA-damage-response pathways are under circadian control [2-4]. Because circadian output processes can feed back into the clock, we investigated whether DNA damage affects the mammalian circadian clock. By using Rat-1 fibroblasts expressing an mPer2 promoter-driven luciferase reporter, we show that ionizing radiation exclusively phase advances circadian rhythms in a dose- and time-dependent manner. Notably, this in vitro finding translates to the living animal, because ionizing radiation also phase advanced behavioral rhythms in mice. The underlying mechanism involves ATM-mediated damage signaling as radiation-induced phase shifting was suppressed in fibroblasts from cancer-predisposed ataxia telangiectasia and Nijmegen breakage syndrome patients. Ionizing radiation-induced phase shifting depends on neither upregulation or downregulation of clock gene expression nor on de novo protein synthesis and, thus, differs mechanistically from dexamethasone- and forskolin-provoked clock resetting [5]. Interestingly, ultraviolet light and tert-butyl hydroperoxide also elicited a phase-advancing effect. Taken together, our data provide evidence that the mammalian circadian clock, like that of the lower eukaryote Neurospora[6], responds to DNA damage and suggest that clock resetting is a universal property of DNA damage.

Ramelteon Phase Advanced Circadian Rhythms of Neuronal Firing in The Suprachiasmatic Nucleus (SCN) Brain Slice by Activation of Both MT 1 and MT 2 Melatonin (MLT) Receptors

Ramelteon, a high affinity MT1 (Ki: 14 pM) and MT2 (Ki: 104 pM) MLT receptor agonist promotes sleep and phase shifts circadian rhythms (Curr Opinion Inv Drugs 1:–121, 2005). This study determined the MLT receptor type(s) involved in ramelteon-mediated phase shifts of spontaneous circadian rhythms of neuronal firing in SCN brain slices from C3H/HeN mice using single-unit recordings. SCN brain slices from wild type (WT) mice showed a peak of neuronal firing at circadian time (CT) 6.1 ± 0.1 h (n=5) [CT12: activity onset for host mice], which was advanced by ramelteon (10 pM, 10 min) application on day 1 at CT 10 to CT 1.2 ± 0.7 h (n=4, p < 0.0001) on day 2. Ramelteon significantly advanced the peak of neuronal firing in SCN from WT (4.9 ± 0.7 h, n=4), MT1KO (3.4 ± 0.15 h, n=5) and MT2KO (1.6 ± 0.4 h, n=3), but not from MT1MT2KO mice. Ramelteon-mediated phase advance in SCN brain slices from WT mice was MLT receptor specific and resulted from activation of MT2 receptors with a smaller contribution from MT1 receptors. MLT (10 pM), however, induced phase advances of identical magnitude via activation of MT2 receptors in SCN from WT (2.7 ± 0.15h, n=4) and MT1 KO (3 ± 0.1h, n=4) mice, but did not affect phase in SCN from MT2KO or MT1MT2KO mice (Hudson et al., Neuropshychopharmacol 30:, 2005). We conclude that ramelteon uncovered a functional MT1 melatonin receptor in the SCN also involved in phase shifting circadian rhythms. Supported by a Takeda Investigator-Sponsored Research Grant 06-016R.

Lack of Food Anticipation in Per2 Mutant Mice

Predicting time of food availability is key for survival in most animals. Under restricted feeding conditions, this prediction is manifested in anticipatory bouts of locomotor activity and body temperature. This process seems to be driven by a food-entrainable oscillator independent of the main, light-entrainable clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus . Although the SCN clockwork involves self-sustaining transcriptional and translational feedback loops based on rhythmic expression of mRNA and proteins of clock genes , the molecular mechanisms responsible for food anticipation are not well understood. Period genes Per1 and Per2 are crucial for the SCN's resetting to light . Here, we investigated the role of these genes in circadian anticipatory behavior by studying rest-activity and body-temperature rhythms of Per1 and Per2 mutant mice under restricted feeding conditions. We also monitored expression of clock genes in the SCN and peripheral tissues. Whereas wild-type and Per1 mutant mice expressed regular food-anticipatory activity, Per2 mutant mice did not show food anticipation. In peripheral tissues, however, phase shifts of clock-gene expression in response to timed food restriction were comparable in all genotypes. In conclusion, a mutation in Per2 abolishes anticipation of mealtime, without interfering with peripheral synchronization by feeding cycles.

An arousing, musically enhanced bird song stimulus mediates circadian rhythm phase advances in dim light

A musically enhanced bird song stimulus presented in the early subjective night phase delays human circadian rhythms. This study determined the phase-shifting effects of the same stimulus in the early subjective day. Eleven subjects (ages 18-63 yr; mean +/- SD: 28.0 +/- 16.6 yr) completed two 4-day laboratory sessions in constant dim light (<20 lux). They received two consecutive presentations of either a 2-h musically enhanced bird song or control stimulus from 0600 to 0800 on the second and third mornings while awake. The 4-day sessions employing either the stimulus or control were counterbalanced. Core body temperature (CBT) was collected throughout the study, and salivary melatonin was obtained every 30 min from 1900 to 2330 on the baseline and poststimulus/postcontrol nights. Dim light melatonin onset and CBT minimum circadian phase before and after stimulus or control presentation was assessed. The musically enhanced bird song stimulus produced significantly larger phase advances of the circadian melatonin (mean +/- SD: 0.87 +/- 0.36 vs. 0.24 +/- 0.22 h) and CBT (1.08 +/- 0.50 vs. 0.43 +/- 0.37 h) rhythms than the control. The stimulus also decreased fatigue and total mood disturbance, suggesting arousing effects. This study shows that a musically enhanced bird song stimulus presented during the early subjective day phase advances circadian rhythms. However, it remains unclear whether the phase shifts are due directly to effects of the stimulus on the clock or are arousal- or dim light-mediated effects. This nonphotic stimulus mediates circadian resynchronization in either the phase advance or delay direction.

The relationship between melatonin and cortisol rhythms: clinical implications of melatonin therapy

AbstractDisturbances in circadian rhythm have been linked to chronic diseases such as insomnia, hypertension, diabetes, and depression. Here we review recent studies on the age‐related changes in cortisol and melatonin rhythms and then present descriptive statistics on our preliminary findings on the rectification of the cortisol rhythms by melatonin therapy in elderly patients with insomnia. In adults, the melatonin onset typically occurs during low cortisol secretion. Administration of exogenous melatonin around dusk will shift the phase of the human circadian clock to earlier hours (advance phase shift) leading to phase advances in circadian rhythms (e.g., sleep, endogenous melatonin, cortisol). With aging, the production of melatonin declines and is shifted to later hours while the production of cortisol increases and its peak occurs earlier in the night. In a randomized placebo‐controlled crossover study with 8 patients with insomnia aged 55 years and older, a group characterized by low and delayed melatonin production, administration of prolonged‐release melatonin in the evening was able to rectify the early onset cortisol production. This delay in nocturnal cortisol onset may explain in part the improvement in sleep quality in elderly patients with insomnia, in schizophrenics, and in depressed patients. Support of circadian pacemaker function by melatonin may provide a new strategy in the treatment of disorders related to impairments in the internal temporal order. The clinical benefit from a decrease in cortisol during the early part of the night may lie beyond the improvement of sleep into a better control of blood pressure, metabolism, and mood. Drug Dev. Res. 65:119–125, 2005. © 2005 Wiley‐Liss, Inc.

The Treatment of Early-Morning Awakening Insomnia With 2 Evenings of Bright Light

To assess the effectiveness of brief bright-light therapy for the treatment of early-morning awakening insomnia. Twenty-four healthy adults with early-morning awakening insomnia were assigned to either the bright-light condition (2,500-lux white light) or the control (dim red light) condition. The circadian phase of rectal temperature and urinary melatonin rhythms were assessed with 26-hour constant routines before and after 2 evenings of light therapy. Sleep and daytime functioning were monitored using sleep diaries, activity monitors, and mood scales before light therapy and for 4 weeks during the follow-up period. While there were no significant circadian phase changes in the dim-light control group, the bright-light group had significant 2-hour phase delays of circadian temperature and melatonin rhythm. Compared to pretreatment measures, over the 4-week follow-up period, the bright-light group had a greater reduction of time awake after sleep onset, showed a trend toward waking later, and had a greater increase of total sleep time. Participants in the bright-light condition also tended to report greater reductions of negative daytime symptoms, including significantly fewer days of feeling depressed at the 4-week follow-up, as compared with the control group. Two evenings of bright-light exposure phase delayed the circadian rhythms of early-morning awakening insomniacs. It also improved diary and actigraphy sleep measures and improved some indexes of daytime functioning for up to 1 month after light exposure. The study suggests that a brief course of evening bright-light therapy can be an effective treatment for early-morning awakening insomniacs who have relatively phase advanced circadian rhythms.

Effect of MT1 melatonin receptor deletion on melatonin‐mediated phase shift of circadian rhythms in the C57BL/6 mouse

In the mouse suprachiasmatic nucleus (SCN), melatonin activates MT1 and MT2 G-protein coupled receptors, which are involved primarily in inhibition of neuronal firing and phase shift of circadian rhythms. This study investigated the ability of melatonin to phase shift circadian rhythms in wild type (WT) and MT1 melatonin receptor knockout (KO) C57BL/6 mice. In WT mice, melatonin (90 microg/mouse, s.c.) administered at circadian time 10 (CT10; CT12 onset of activity) significantly phase advanced the onset of the circadian activity rhythm (0.60 +/- 0.09 hr, n = 41) when compared with vehicle treated controls (-0.02 +/- 0.07 hr, n = 28) (P < 0.001). In contrast, C57 MT1KO mice treated with melatonin did not phase shift circadian activity rhythms (-0.10 +/- 0.12 hr, n = 42) when compared with vehicle treated mice (-0.12 +/- 0.07 hr, n = 43). Similarly, in the C57 MT1KO mouse melatonin did not accelerate re-entrainment to a new dark onset after an abrupt advance of the dark cycle. In contrast, melatonin (3 and 10 pm) significantly phase advanced circadian rhythm of neuronal firing in SCN brain slices independent of genotype with an identical maximal shift at 10 pm (C57 WT: 3.61 +/- 0.38 hr, n = 3; C57 MT(1)KO: 3.45 +/- 0.11 hr, n = 4). Taken together, these results suggest that melatonin-mediated phase advances of circadian rhythms of neuronal firing in the SCN in vitro may involve activation of the MT2 receptor while in vivo activation of the MT1 and possibly the MT2 receptor may be necessary for the expression of melatonin-mediated phase shifts of overt circadian activity rhythms.

24-h Monitoring of plasma norepinephrine, MHPG, cortisol, growth hormone and prolactin in depression

Depression is associated with alterations in hormone and catecholamine circadian rhythms. Analysis of these alterations has the potential to distinguish between three neurobiological models of depression, the catecholamine model, the phase advance model and the dysregulation model. Although a number of studies of 24-h rhythms have been reported, inconsistencies among the findings have complicated efforts to model the chronobiology of depression. The present study takes advantage of frequent plasma sampling over the 24-h period and a multioscillator cosinor model to fit the 24-h rhythms. Method: Plasma levels of norepinephrine, cortisol, prolacatin and growth hormone were sampled at 30-min intervals, and MHPG at 60-min intervals, over a 24-h period in 22 patients with major depressive disorder and 20 healthy control volunteers. Results: The depressed patients had phase advanced circadian rhythms for cortisol, norepinephrine and MHPG, phase advanced hemicircadian rhythms for cortisol and prolactin, and a phase advanced ultradian rhythm for prolactin compared to healthy control subjects. In addition, the rhythm-corrected 24-h mean value (mesor) of norepinephrine was lower in the depressed patients compared to the healthy controls. There also was a poorer goodness-of-fit for norepinephrine to the circadian oscillator in the depressed patients relative to the healthy controls. Conclusions: These findings provide partial support for the dysregulation model of depression and are consistent with those studies that have found phase advances in cortisol, norepinephrine and MHPG rhythms in depression.

Seasonal affective disorder

The fascinating phenomena of recurrent winter depression and its successful treatment by light continues to elicit extensive research worldwide. Although our understanding of the epidemiology of the disorder and of the efficacy of light grows, the underlying pathophysiology of the disorder and the physical mechanism of light's effects remain an intellectual and scientific puzzle. Phase-advanced circadian rhythms and disordered serotonin regulation remain the physiologic mechanisms of greatest study.

Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms.

This study demonstrates the involvement of the MT2 (Mel1b) melatonin receptor in mediating phase advances of circadian activity rhythms by melatonin. In situ hybridization histochemistry with digoxigenin-labeled oligonucleotide probes revealed for the first time the expression of mt1 and MT2 melatonin receptor mRNA within the suprachiasmatic nucleus of the C3H/HeN mouse. Melatonin (0.9 to 30 microg/mouse, s.c.) administration during 3 days at the end of the subjective day (CT 10) to C3H/HeN mice kept in constant dark phase advanced circadian rhythms of wheel running activity in a dose-dependent manner [EC50=0.72 microg/mouse; 0.98+/-0.08 h (n=15) maximal advance at 9 microg/mouse]. Neither the selective MT2 melatonin receptor antagonists 4P-ADOT and 4P-PDOT (90 microg/mouse, s.c.) nor luzindole (300 microg/mouse, s.c.), which shows 25-fold higher affinity for the MT2 than the mt1 subtype, affected the phase of circadian activity rhythms when given alone at CT 10. All three antagonists, however, shifted to the right the dose-response curve to melatonin, as they significantly reduced the phase shifting effects of 0.9 and 3 microg melatonin. This is the first study to demonstrate that melatonin phase advances circadian rhythms by activation of a membrane-bound melatonin receptor and strongly suggests that this effect is mediated through the MT2 melatonin receptor subtype within the circadian timing system. We conclude that the MT2 melatonin receptor subtype is a novel therapeutic target for the development of subtype-selective analogs for the treatment of circadian sleep and mood-related disorders.

Early evening melatonin and S-20098 advance circadian phase and nocturnal regulation of core body temperature

The phase-shifting capacity and thermoregulatory effects of a single oral administration at 18 h of melatonin (5 mg) or S-20098, a melatonin agonist (5 or 100 mg), was investigated in eight healthy young men in a double-blind placebo crossover design. The unmasking conditions of a shortened constant-routine protocol (mini-CR) were used to collect evening phase markers of physiological parameters. In comparison to placebo, all three drug administrations induced an earlier dim-light melatonin onset (DLMO), an earlier increase in distal skin temperature, and an earlier decrease in core body temperature (CBT), heart rate, and proximal skin temperature. This indicates that administration at 18 h of both melatonin and S-20098 (more pronounced with 100 than 5 mg) induced an earlier regulation of the endogenous circadian nocturnal decline in CBT. On the posttreatment day a second mini-CR revealed persistent significantly phase-advanced circadian rhythms as estimated by DLMO, as well as by the midrange crossing time of CBT and heart rate decline. There were no significant differences between the two doses of S-20098. The data suggest that, in addition to immediate thermoregulatory changes, a phase advance of the circadian system had occurred and that the phase advance could still be measured on the posttreatment day.

Circadian rhythms of early morning awakening insomniacs

It has been suggested that two types of insomnia, sleep onset insomnia and early morning awakening insomnia, may be caused by delays and advances respectively of circadian rhythms. Evidence supports the circadian rhythm phase delay of sleep onset insomniacs. The present study investigated the phase timing of circadian rhythms of early morning awakening insomniacs compared with a group of age matched good sleepers. A 24-h bed rest laboratory session was used to evaluate the endogenous core body temperature and urinary melatonin rhythms. Objective and subjective sleepiness were also measured every 30 min across the session with 10 min multiple sleep latency tests and Stanford Sleepiness Scale. Maximum and minimum phases of each individual's rhythm were identified using two-component cosine curve fitting. Compared with the good sleepers, the insomniacs had significant phase advances of 2-4 h for the temperature and melatonin rhythms. However, the 0-4 h advances of the sleepiness rhythms were not significant. This latter unexpected result was explained on the basis of variability of sleepiness measures. It was suggested that early morning awakening insomnia arises from phase advanced circadian rhythms which evoke early arousal's from sleep.

Vitamin B 12 affects non-photic entrainment of circadian locomotor activity rhythms in mice

Administration of vitamin B 12 (VB12) has been reported to normalize human sleep-wake rhythm disorders such as non-24-h sleep-wake syndrome (HNS), delayed sleep phase syndrome (DSPS) or insomnia. However, the mechanisms of the action of VB 12 on the rhythm disorders are unknown. In the present study, therefore, effects of VB 12 on circadian rhythms of locomotor activity were examined in mice. In the first experiment, CBA/J mice were maintained under continuous light condition (LL) or blinded, and after free-running rhythms became stable, the mice were intraperitoneally injected with either VB12 or saline at a fixed time every day. In all the mice with τ > 24 h, saline injections resulted in entrainment of circadian rhythms, whereas not all the mice with τ < 24 h entrained to the injection. In contrast to saline injections, VB12 injections did not always induce entrainment and about half of the mice with τ > 24 h free-ran during the injection. In the second experiment, the amount of phase advances of circadian rhythms induced by a single injection of saline at circadian time (CT) 11 under LL was compared between the mice with and without VB 12 silastic tubes. The results showed that the amplitude of phase advances was smaller in the mice with VB 12 than those without V1312. In the third experiment, daily injections of saline were given to the mice with VB12 silastic tubes maintained under LL. In this chronic treatment of VB12 as well, attenuating effects of VB 12 on saline-induced entrainment were observed. These results suggest that VB 12 affects the mechanisms implicated in non-photic entrainment of circadian rhythms in mice.