Circadian rhythms and hormonal homeostasis: Pathophysiological implications

Over recent years, a deeper comprehension of the molecular mechanisms that control biological clocks and circadian rhythms has been achieved. In fact, many studies have contributed to unravelling the importance of the molecular clock for the regulation of our physiology, including hormonal and metabolic homeostasis. Here we will review the structure, organisation and molecular machinery that make our circadian clock work, and its relevance for the proper functioning of physiological processes. We will also describe the interconnections between circadian rhythms and endocrine homeostasis, as well as the underlying consequences that circadian dysregulations might have in the development of several pathologic affections. Finally, we will discuss how a better knowledge of such relationships might prove helpful in designing new therapeutic approaches for endocrine and metabolic diseases

Lighting as a Circadian Rhythm-Entraining and Alertness-Enhancing Stimulus in the Submarine Environment

The human brain can only accommodate a circadian rhythm that closely follows 24 hours. Thus, for a work schedule to meet the brain’s hard-wired requirement, it must employ a 24 hour-based program. However, the 6 hours on, 12 hours off (6/12) submarine watchstanding schedule creates an 18-hour “day” that Submariners must follow. Clearly, the 6/12 schedule categorically fails to meet the brain’s operational design, and no schedule other than one tuned to the brain’s 24 hour rhythm can optimize performance. Providing Submariners with a 24 hour-based watchstanding schedule—combined with effective circadian entrainment techniques using carefully-timed exposure to light—would allow crewmembers to work at the peak of their daily performance cycle and acquire more restorative sleep. In the submarine environment, where access to natural light is absent, electric lighting can play an important role in actively entraining—and closely maintaining—circadian regulation. Another area that is likely to have particular importance in the submarine environment is the potential effect of light to help restore or maintain alertness

Genetic basis of human circadian rhythm disorders.

Circadian rhythm disorders constitute a group of phenotypes that usually present as altered sleep-wake schedules. Until a human genetics approach was applied to investigate these traits, the genetic components regulating human circadian rhythm and sleep behaviors remained mysterious. Steady advances in the last decade have dramatically improved our understanding of the genes involved in circadian rhythmicity and sleep regulation. Finding these genes presents new opportunities to use a wide range of approaches, including in vitro molecular studies and in vivo animal modeling, to elevate our understanding of how sleep and circadian rhythms are regulated and maintained. Ultimately, this knowledge will reveal how circadian and sleep disruption contribute to various ailments and shed light on how best to maintain and recover good health

Robustness from flexibility in the fungal circadian clock

Background Robustness is a central property of living systems, enabling function to be maintained against environmental perturbations. A key challenge is to identify the structures in biological circuits that confer system-level properties such as robustness. Circadian clocks allow organisms to adapt to the predictable changes of the 24-hour day/night cycle by generating endogenous rhythms that can be entrained to the external cycle. In all organisms, the clock circuits typically comprise multiple interlocked feedback loops controlling the rhythmic expression of key genes. Previously, we showed that such architectures increase the flexibility of the clock's rhythmic behaviour. We now test the relationship between flexibility and robustness, using a mathematical model of the circuit controlling conidiation in the fungus Neurospora crassa. Results The circuit modelled in this work consists of a central negative feedback loop, in which the frequency (frq) gene inhibits its transcriptional activator white collar-1 (wc-1), interlocked with a positive feedback loop in which FRQ protein upregulates WC-1 production. Importantly, our model reproduces the observed entrainment of this circuit under light/dark cycles with varying photoperiod and cycle duration. Our simulations show that whilst the level of frq mRNA is driven directly by the light input, the falling phase of FRQ protein, a molecular correlate of conidiation, maintains a constant phase that is uncoupled from the times of dawn and dusk. The model predicts the behaviour of mutants that uncouple WC-1 production from FRQ's positive feedback, and shows that the positive loop enhances the buffering of conidiation phase against seasonal photoperiod changes. This property is quantified using Kitano's measure for the overall robustness of a regulated system output. Further analysis demonstrates that this functional robustness is a consequence of the greater evolutionary flexibility conferred on the circuit by the interlocking loop structure. Conclusions Our model shows that the behaviour of the fungal clock in light-dark cycles can be accounted for by a transcription-translation feedback model of the central FRQ-WC oscillator. More generally, we provide an example of a biological circuit in which greater flexibility yields improved robustness, while also introducing novel sensitivity analysis techniques applicable to a broader range of cellular oscillators

Circadian Phase Resetting via Single and Multiple Control Targets

Circadian entrainment is necessary for rhythmic physiological functions to be appropriately timed over the 24-hour day. Disruption of circadian rhythms has been associated with sleep and neuro-behavioral impairments as well as cancer. To date, light is widely accepted to be the most powerful circadian synchronizer, motivating its use as a key control input for phase resetting. Through sensitivity analysis, we identify additional control targets whose individual and simultaneous manipulation (via a model predictive control algorithm) out-perform the open-loop light-based phase recovery dynamics by nearly 3-fold. We further demonstrate the robustness of phase resetting by synchronizing short- and long-period mutant phenotypes to the 24-hour environment; the control algorithm is robust in the presence of model mismatch. These studies prove the efficacy and immediate application of model predictive control in experimental studies and medicine. In particular, maintaining proper circadian regulation may significantly decrease the chance of acquiring chronic illness

Taking the lag out of jet lag through model-based schedule design

Travel across multiple time zones results in desynchronization of environmental time cues and the sleep–wake schedule from their normal phase relationships with the endogenous circadian system. Circadian misalignment can result in poor neurobehavioral performance, decreased sleep efficiency, and inappropriately timed physiological signals including gastrointestinal activity and hormone release. Frequent and repeated transmeridian travel is associated with long-term cognitive deficits, and rodents experimentally exposed to repeated schedule shifts have increased death rates. One approach to reduce the short-term circadian, sleep–wake, and performance problems is to use mathematical models of the circadian pacemaker to design countermeasures that rapidly shift the circadian pacemaker to align with the new schedule. In this paper, the use of mathematical models to design sleep–wake and countermeasure schedules for improved performance is demonstrated. We present an approach to designing interventions that combines an algorithm for optimal placement of countermeasures with a novel mode of schedule representation. With these methods, rapid circadian resynchrony and the resulting improvement in neurobehavioral performance can be quickly achieved even after moderate to large shifts in the sleep–wake schedule. The key schedule design inputs are endogenous circadian period length, desired sleep–wake schedule, length of intervention, background light level, and countermeasure strength. The new schedule representation facilitates schedule design, simulation studies, and experiment design and significantly decreases the amount of time to design an appropriate intervention. The method presented in this paper has direct implications for designing jet lag, shift-work, and non-24-hour schedules, including scheduling for extreme environments, such as in space, undersea, or in polar regions

An isostable coordinate based amelioration strategy to mitigate the effects of Jet lag

Commercial air travel has become extremely commonplace in the last 20 to 30 years especially as the world has moved towards new heights of globalization. Though air travel has greatly reduced transit times allowing people to cover thousand of miles within hours, it comes with its fair share of issues. jet-lag can be regarded to be at the top of those list of problems; jet-lag typically results from rapid travel through multiple time zones which causes a significant misalignment between the person\u27s internal circadian clock and the external time. A person\u27s circadian clock is governed by a population of coupled neurons entrained to a 24-hour light and dark cycle and thus after rapid air travel, the neuron population needs a certain time to get accustomed to the new time zone. This misalignment can result in a variety of health problems including, but not limited to, lethargy, insomnia and adverse effects to the sleep cycle. Various techniques have been proposed and are currently in use for jet-lag treatment like melatonin ingestion or making drastic changes to one\u27s own routine prior to air travel. However, these treatment strategies are normally accompanied with long re-entrainment times or following a strict schedule to help with correcting the sleep cycle. The presented work explores an alternate strategy for jet-lag treatment using the notion of operational phase and isostable coordinates for model reduction and then, applying optimal control to derive inputs which can be applied directly to the model. To show the framework\u27s efficacy, results are presented by applying the strategy to a 2-d model; preliminary results show that the proposed approach greatly reduces the reentrainment time required to acclimatize to the new time zone