Circadian Clock

Huntington's disease (HD) is a fatal genetic neurodegenerative disorder caused by a CAG triplet repeat expansion in the gene encoding the protein huntingtin. The most studied model of HD, the R6/2 transgenic mouse, replicates many features of the disease. In addition to motor, cognitive, and endocrine dysfunctions, these mice exhibit a progressive disruption of circadian rhythms. This is accompanied by an altered expression of the circadian clock genes in the suprachiasmatic nucleus/nuclei (SCN), the principal circadian pacemaker in the brain. The neuropeptide vasoactive intestinal polypeptide (VIP) and its receptor VPAC2 are highly expressed in the SCN, and VIPergic signaling plays an essential role in maintenance of ongoing circadian rhythmicity. We found a marked reduction in both VIP mRNA and VPAC2 receptor mRNA, quantified by RT-PCR, as well as a decrease in VIP immunostaining in the SCN of R6/2 mice. These changes were coupled to a disruption of circadian rhythm. We observ...

In mammals, daily rhythms in behaviour and physiology are driven by a circadian timing system comprised, in a hierarchical way, of a master pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus and of peripheral oscillators in most body cells. At the molecular level, in both the SCN and peripheral oscillators, the circadian clock mechanism is built from interconnected feedback loops in gene expression that operate in a cell-autonomous and self-sustained fashion. The SCN clock is mainly entrained by light/dark cycles. By contrast, peripheral oscillators can be strongly affected by daily feeding cycles, which have little effect on the phase of the SCN. However, when feeding schedules are coupled with a caloric restriction, behavioural and physiological circadian rhythms and gene expression in the SCN are shifted and/or entrained to meal-time. Moreover, the reward and motivational value of food can also be a potent synchroniser for the SCN clock. This suggests that energy metabolism and motivational properties of food can influence the clock mechanism of the SCN. Food-related cues may entrain clock genes of the SCN with a direct effect, or be mediated indirectly by another neural or peripheral site. In addition, there may be one or more oscillator sites that would play an integral role as a food-entrained oscillator (FEO), responsible for anticipation of meal-time. The site housing, or the network underlying, this putative FEO is still unknown. The aim of this review is to summarise our current knowledge of the central and peripheral circadian clocks and how they can be entrained by feeding at the physiological and molecular levels.

Addiction is a widespread public health issue with social and economic ramifications. Substance abuse disorders are often accompanied by disruptions in circadian rhythms including sleep/wake cycles, which can exacerbate symptoms of addiction and dependence. Additionally, genetic disturbance of circadian molecular mechanisms can predispose some individuals to substance abuse disorders. In this review, we will discuss how circadian genes can regulate midbrain dopaminergic activity and subsequently, drug intake and reward. We will also suggest future directions for research on circadian genes and drugs of abuse.

Sleep is an essential physiological process which profoundly affects a wide range of biological activities. It is now known that sleep supports myriad vital functions in the central nervous system. This includes neural plasticity, learning, memory, cognition and emotional regulation. Additionally, it affects basic processes such as cardiovascular, immunological, and metabolic activity. Evidence from multiple lines of research has thus shown that good quality of sleep is essential for both survival and optimal functioning of life. Considerable evidence also supports the conclusion that even minimal dysfunctions in circadian regulation can significantly disrupt sleep and broadly affect body physiology. As a consequence, it is now appreciated that the therapy of sleep disorders is more complex than was once thought. At present, several clinical disciplines have recognized the significance of the biological clock in health and illness and are incorporating this knowledge into treatment programs. Recent decades have seen the emergence of chronotherapies, i.e., treatment strategies that are aimed at producing adjustments in the circadian clock. The final objective of these approaches is to affect basic cellular and physiological processes, which in turn may be at the root of disorders in, e.g., , immune functioning, metabolic activity, and psychiatric disturbance. It is suggested that the integration of chronobiological perspectives into mainstream medical disciplines would be of significant benefit, both for the reduction of the prevalence of diseases and their treatment. This review considers the physiology of sleep and the importance of timekeeping mechanisms in the regulation of the overall health of individuals.

Young sunflower plants track the Sun from east to west during the day and then reorient during the night to face east in anticipation of dawn. In contrast, mature plants cease movement with their flower heads facing east. We show that circadian regulation of directional growth pathways accounts for both phenomena and leads to increased vegetative biomass and enhanced pollinator visits to flowers. Solar tracking movements are driven by antiphasic patterns of elongation on the east and west sides of the stem. Genes implicated in control of phototropic growth, but not clock genes, are differentially expressed on the opposite sides of solar tracking stems. Thus, interactions between environmental response pathways and the internal circadian oscillator coordinate physiological processes with predictable changes in the environment to influence growth and reproduction.

In humans, a person’ s chronotype depends on environmental cues and on individual characteristics, with late chronotypes prevailing in youth. Social jetlag (SJL), the misalignment between an individual's biological clock and social time , is higher in late chronotypes. Strong SJL is expected in Uruguayan university students with morning class schedules and very late entertainment activities. Sleep disorders have been reported in Antarctic inhabitants, that might be a response to the extreme environment or to the strictness of Antarctic life. We evaluated, for the first time in Uruguay, the chronotypes and SJL of 17 undergraduate students of the First Uruguayan Summer School on Antarctic Research, using Munich Chronotype Questionnaire (MCTQ) and sleep logs (SL) recorded during 3 phases: pre-Antarctic, Antarctic,
and post-Antarctic. The midsleep point of free days corrected for sleep debt on work days (MSFsc,) was used as proxy of individuals’ chronotype, whose values (around 6 a.m.) are the latest ever reported. We found a SJL of around 2 h in average, which correlated positively with MSFsc, confirming that late chronotypes generate a higher sleep debt during weekdays. Midsleep point and sleep duration significantly decreased between pre-Antarctic and Antarctic phases, and sleep duration rebounded to significant higher values in the postAntarctic phase. Waking time, but not sleep onset time, significantly varied among phases.
This evidence suggests that sleep schedules more likely depended on the social agenda than on the environmental light–dark shifts. High motivation of students towards Antarctic activities likely induced a subjective perception of welfare non-dependent on sleep duration

Endogenous clocks control the rhythm of many biological processes. Malfunction of endogenous clocks in humans can lead to various diseases as sleep disorders, depres­sions, the metabolic syndrome and cancer. All animals have a main clock in the brain. This clock comprises a network of clock neurons that communicate with each other. In each clock neuron, conserved clock genes and pro­teins interact in to generate a molecular os­cillation. The molecular basis of this rhythm generation as well as the anatomy of the neuronal clock network is best investigated in the fruit fly Drosophila melanogaster. In the little fly, clock genes can be shut down in specific clock neurons. Furthermore, specific clock neurons can be electrically silenced and the rhythmic behaviour of such manipulated flies can be studied. A flurry of recent studies has begun to identify the role of specific clock neurons in the clock network, and these find­ings are helping to understand the basic neu­ronal mechanisms o...

A vast majority of the pathophysiological and metabolic processes in humans are
temporally controlled by a master circadian clock located centrally in the hypothalamic
suprachiasmatic nucleus of the brain, as well as by specialized peripheral oscillators
located in other body tissues. This circadian clock system generates a rhythmical
diurnal transcriptional-translational cycle in clock genes and protein expression and
activities regulating numerous downstream target genes. Clock genes as key regulators
of physiological function and dysfunction of the circadian clock have been linked
to various diseases and multiple morbidities. Emerging omics technologies permits
largescale multi-dimensional investigations of the molecular landscape of a given
disease and the comprehensive characterization of its underlying cellular components
(e.g., proteins, genes, lipids, metabolites), their mechanism of actions, functional
networks and regulatory systems. Ultimately, they can be used to better understand
disease and interpatient heterogeneity, individual profile, identify personalized targetable key molecules and pathways, discover novel biomarkers and genetic alterations, which collectively can allow for a better patient stratification into clinically relevant subgroups to improve disease prediction and prevention, early diagnostic, clinical outcomes, therapeutic benefits, patient’s quality of life and survival. The use of
“omics” technologies has allowed for recent breakthroughs in several scientific
domains, including in the field of circadian clock biology. Although studies have
explored the role of clock genes using circadiOmics (which integrates circadian
omics, such as genomics, transcriptomics, proteomics and metabolomics) in human
disease, no such studies have investigated the implications of circadian disruption
in oral, head and neck pathologies using multi-omics approaches and linking the
omics data to patient-specific circadian profiles. There is a burgeoning body of
evidence that circadian clock controls the development and homeostasis of oral
and maxillofacial structures, such as salivary glands, teeth and oral epithelium.
Hence, in the current era of precision medicine and dentistry and patient-centered
health care, it is becoming evident that a multi-omics approach is needed to
improve our understanding of the role of circadian clock-controlled key players in the regulation of head and neck pathologies. This review discusses current knowledge on
the role of the circadian clock and the contribution of omics-based approaches toward
a novel precision health era for diagnosing and treating head and neck pathologies, with an emphasis on oral, head and neck cancer and Sjögren’s syndrome.

The survival and reproduction of plants depend on their ability to cope with a wide range of daily and seasonal environmental fluctuations during their life cycle. Phytohormones are plant growth regulators that are involved in almost every aspect of growth and development as well as plant adaptation to myriad abiotic and biotic conditions. The circadian clock, an endogenous and cell-autonomous biological timekeeper that produces rhythmic outputs with close to 24-h rhythms, provides an adaptive advantage by synchronizing plant physiological and metabolic processes to the external environment. The circadian clock regulates phytohormone biosynthesis and signaling pathways to generate daily rhythms in hormone activity that fine-tune a range of plant processes, enhancing adaptation to local conditions. This review explores our current understanding of the interplay between the circa-dian clock and hormone signaling pathways.