Plasticity in the period of the circadian pacemaker induced by phase dispersion of its constituent cellular clocks

The mammalian circadian pacemaker is commonly thought to be a rigid oscillator that generates output under a variety of circumstances that differ only in phase, period, and/or amplitude. Yet the pacemaker is composed of many cells that each can respond to varying circumstances in different ways. Computer simulations demonstrate that networks of such pacemaker cells behave differently under a light-dark cycle compared with constant darkness. The differences demonstrate that the circadian pacemaker is plastic: The pacemaker shapes its properties in response to the circumstances. A consequence is that properties of a pacemaker under a light-dark cycle cannot be derived from studies of the same system in constant darkness. In this paper we show that the dispersion of phase in a network of coupled oscillators can influence ensemble period: For the considered type of coupling, it is demonstrated that the more synchronous the cells are, the longer is the ensemble period. This is consistent with various data sets obtained in mammals, and even with a data set from fruit flies, in which circadian variation in behavior is regulated in a distinctly differently way from that in mammals. We conclude that environmental circumstances such as photoperiod and exposure to light pulses in otherwise darkness modify the phase distribution of the network and, thereby, the period of the ensemble. Our study supports the view that such properties as circadian period are not solely determined by clock genes but are also determined by the genes that regulate the communication in cellular networks

Pacer cell response to periodic Zeitgebers

Almost all organisms show some kind of time periodicity in their behavior. Especially in mammals the neurons of the suprachiasmatic nucleus form a biological clock regulating the activity-inactivity cycle of the animal. This clock is stimulated by the natural 24-hour light-dark cycle. In our model of this system we consider each neuron as a so called phase oscillator, coupled to other neurons for which the light-dark cycle is a Zeitgeber. To simplify the model we first take an externally stimulated single phase oscillator. The first part of the phase interval is called the active state and the remaining part is the inactive state. Without external stimulus the oscillator oscillates with its intrinsic period. An external stimulus, be it from activity of neighboring cells or the periodic daylight cycle, acts twofold, it may delay the change form active to inactive and it may advance the return to the active state. The amount of delay and advance depends on the strength of the stimulus. We use a circle map as a mathematical model for this system. This map depends on several parameters, among which the intrinsic period and phase delay and advance. In parameter space we find Arnol'd tongues where the system is in resonance with the Zeitgeber. Thus already in this simplified system we find entrainment and synchronization. Also some other phenomena from biological experiments and observations can be related to the dynamical behavior of the circle map

Daytime melatonin and light independently affect human alertness and body temperature

Light significantly improves alertness during the night (Cajochen, Sleep Med Rev, 11, 2007 and 453; Ruger et al., AJP Regul Integr Comp Physiol, 290, 2005 and R1413), but results are less conclusive at daytime (Lok et al., J Biol Rhythms, 33, 2018 and 589). Melatonin and core body temperature levels at those times of day may contribute to differences in alerting effects of light. In this experiment, the combined effect of daytime exogenous melatonin administration and light intensity on alertness, body temperature, and skin temperature was studied. The goal was to assess whether (a) alerting effects of light are melatonin dependent, (b) soporific effects of melatonin are mediated via the thermoregulatory system, and (c) light can improve alertness after melatonin-induced sleepiness during daytime. 10 subjects (5 females, 5 males) received melatonin (5 mg) in dim (10 lux) and, on a separate occasion, in bright polychromatic white light (2000 lux). In addition, they received placebo both under dim and bright light conditions. Subjects participated in all four conditions in a balanced order, yielding a balanced within-subject design, lasting from noon to 04:00 pm. Alertness and performance were assessed half hourly, while body temperature and skin temperature were measured continuously. Saliva samples to detect melatonin concentrations were collected half hourly. Melatonin administration increased melatonin concentrations in all subjects. Subjective sleepiness and distal skin temperature increased after melatonin ingestion. Bright light exposure after melatonin administration did not change subjective alertness scores, but body temperature and proximal skin temperature increased, while distal skin temperature decreased. Light exposure did not significantly affect these parameters in the placebo condition. These results indicate that (a) exogenous melatonin administration during daytime increases subjective sleepiness, confirming a role for melatonin in sleepiness regulation, (b) bright light exposure after melatonin ingestion significantly affected thermoregulatory parameters without altering subjective sleepiness, therefore temperature changes seem nonessential for melatonin-induced sleepiness, (c) subjective sleepiness was increased by melatonin ingestion, but bright light administration was not able to improve melatonin-induced sleepiness feelings nor performance. Other (physiological) factors may therefore contribute to differences in alerting effects of light during daytime and nighttime

Light, alertness, and alerting effects of white light:A literature overview

Light is known to elicit non-image-forming responses, such as effects on alertness. This has been reported especially during light exposure at night. Nighttime results might not be translatable to the day. This article aims to provide an overview of (1) neural mechanisms regulating alertness, (2) ways of measuring and quantifying alertness, and (3) the current literature specifically regarding effects of different intensities of white light on various measures and correlates of alertness during the daytime. In general, the present literature provides inconclusive results on alerting effects of the intensity of white light during daytime, particularly for objective measures and correlates of alertness. However, the various research paradigms employed in earlier studies differed substantially, and most studies tested only a limited set of lighting conditions. Therefore, the alerting potential of exposure to more intense white light should be investigated in a systematic, dose-dependent manner with multiple correlates of alertness and within one experimental paradigm over the course of day

Linking light exposure and subsequent sleep:A field polysomnography study in humans

Study objectives: To determine the effect of light exposure on subsequent sleep characteristics under ambulatory field conditions. Methods: Twenty healthy participants were fitted with ambulatory PSG and wrist-actigraphs to assess light exposure, rest-activity, sleep quality, timing and architecture. Laboratory salivary dim-light melatonin onset (DLMO) was analyzed to determine endogenous circadian phase. Results: Later circadian clock phase was associated with lower intensity (R2=0.34, χ2(1)=7.19, p <0.01), later light exposure (quadratic, controlling for daylength, R2=0.47, χ2(3)=32.38, p <0.0001), and to later sleep timing (R2=0.71, χ2(1)=20.39, p<0.0001). Those with later first exposure to more than 10 lux of light had more awakenings during subsequent sleep (controlled for daylength, R2=0.36, χ2(2)=8.66, p<0.05). Those with later light exposure subsequently had a shorter latency to first REM sleep episode (R2=0.21, χ2(1)=5.77, p<0.05). Those with less light exposure subsequently had a higher percentage of REM sleep (R2=0.43, χ2(2)=13.90, p<0.001) in a clock phase modulated manner. Slow wave sleep accumulation was observed to be larger after preceding exposure to high maximal intensity and early first light exposure (p<0.05). Conclusions: The quality and architecture of sleep is associated with preceding light exposure. We propose that light exposure timing and intensity does not only modulate circadian-driven aspects of sleep but also homeostatic sleep pressure. These novel ambulatory PSG findings are the first to highlight the direct relationship between light and subsequent sleep, combining knowledge of homeostatic and circadian regulation of sleep by light. Upon confirmation by interventional studies, this hypothesis could change current understanding of sleep regulation and its relationship to prior light exposure

Phylogeny and oscillating expression of period and cryptochrome in short and long photoperiods suggest a conserved function in Nasonia vitripennis

Photoperiodism, the ability to respond to seasonal varying day length with suitable life history changes, is a common trait in organisms that live in temperate regions. In most studied organisms, the circadian system appears to be the basis for photoperiodic time measurement. In insects this is still controversial: while some data indicate that the circadian system is causally involved in photoperiodism, others suggest that it may have a marginal or indirect role. Resonance experiments in the parasitic wasp Nasonia vitripennis have revealed a circadian component in photoperiodic time measurement compatible with a mechanism of internal coincidence where a two components oscillator system obtains information from dawn and dusk, respectively. The identity of this oscillator (or oscillators) is still unclear but possible candidates are the oscillating molecules of the auto-regulatory feedback loops in the heart of the circadian system. Here, we show for the first time the circadian oscillation of period and cryptochrome mRNAs in the heads of Nasonia females kept under short and long photoperiods. Period and cryptochrome mRNA levels display a synchronous oscillation in all conditions tested and persist, albeit with reduced amplitude, during the first day in constant light as well as constant darkness. More importantly, the signal for the period and cryptochrome oscillations is set by the light-on signal. These results, together with phylogenetic analyses, indicate that Nasonia’s period and cryptochrome display characteristics of homologous genes in other hymenopteran species

Daily light exposure patterns reveal phase and period of the human circadian clock

Light is the most potent time cue that synchronizes (entrains) the circadian pacemaker to the 24-h solar cycle. This entrainment process is an interplay between an individual's daily light perception and intrinsic pacemaker period under free-running conditions. Establishing individual estimates of circadian phase and period can be time-consuming. We show that circadian phase can be accurately predicted (SD = 1.1 h for dim light melatonin onset, DLMO) using 9 days of ambulatory light and activity data as an input to Kronauer's limit-cycle model for the human circadian system. This approach also yields an estimated circadian period of 24.2 h (SD = 0.2 h), with longer periods resulting in later DLMOs. A larger amount of daylight exposure resulted in an earlier DLMO. Individuals with a long circadian period also showed shorter intervals between DLMO and sleep timing. When a field-based estimation of tau can be validated under laboratory studies in a wide variety of individuals, the proposed methods may prove to be essential tools for individualized chronotherapy and light treatment for shift work and jetlag applications. These methods may improve our understanding of fundamental properties of human circadian rhythms under daily living conditions