Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.

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The mammalian circadian timing system: organization and coordination of central and peripheral clocks.

Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus. Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases. Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature. At the level of individual tissues, thousands of genes are brought to unique phases through the actions of a local transcription/translation-based feedback oscillator and systemic cues. In this molecular clock, the proteins CLOCK and BMAL1 cause the transcription of genes which ultimately feedback and inhibit CLOCK and BMAL1 transcriptional activity. Finally, there are also other molecular circadian oscillators which can act independently of the transcription-based clock in all species which have been tested.

https://www.springer.com/cda/content/document/cda_downloaddocument/9783642259494-c1.pdf?SGWID=0-0-45-1387410-p174273964

Molecular components of the mammalian circadian clock

Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.

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The Genetics of Mammalian Circadian Order and Disorder: Implications for Physiology and Disease

Mice deficient in the circadian transcription factor BMAL1 (brain and muscle ARNT-like protein) have impaired circadian behavior and demonstrate loss of rhythmicity in the expression of target genes. Here we report that Bmal1(-/-) mice have reduced lifespans and display various symptoms of premature aging including sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others. The early aging phenotype correlates with increased levels of reactive oxygen species in some tissues of the Bmal1(-/- )animals. These findings, together with data on CLOCK/BMAL1-dependent control of stress responses, may provide a mechanistic explanation for the early onset of age-related pathologies in the absence of BMAL1.

/pdf/early-aging-and-age-related-pathologies-in-mice-deficient-in-3l139ko0r9.pdf

Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock

Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature At the level of individual tissues, thousands of genes are brought to unique phases through the actions of a local transcription/translation-based feedback oscillator and systemic cues In this molecular clock, the proteins CLOCK and BMAL1 cause the transcription of genes which ultimately feedback and inhibit CLOCK and BMAL1 transcriptional activity Finally, there are also other molecular circadian oscillators which can act independently of the transcription-based clock in all species which have been tested

/pdf/molecular-components-of-the-mammalian-circadian-clock-12hhkp0nfg.pdf

Molecular components of the Mammalian circadian clock

Period (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2Brdm1 mutant mice, which have a deletion in the PAS domain of the Per2 protein, show alterations in the glutamatergic system. Lowered expression of the glutamate transporter Eaat1 is observed in these animals, leading to reduced uptake of glutamate by astrocytes. As a consequence, glutamate levels increase in the extracellular space of Per2Brdm1 mutant mouse brains. This is accompanied by increased alcohol intake in these animals. In humans, variations of the PER2 gene are associated with regulation of alcohol consumption. Acamprosate, a drug used to prevent craving and relapse in alcoholic patients is thought to act by dampening a hyper-glutamatergic state. This drug reduced augmented glutamate levels and normalized increased alcohol consumption in Per2Brdm1 mutant mice. Collectively, these data establish glutamate as a link between dysfunction of the circadian clock gene Per2 and enhanced alcohol intake.

/pdf/the-clock-gene-per2-influences-the-glutamatergic-system-and-1g8ao6nqw5.pdf

The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption.

The periodic succession of night and day has influenced life on earth for millions of years. Many organisms have "internalized" this periodic change in the form of the circadian clock. Its main function is to organize the time course of biochemical, physiological and behavioural processes thereby optimizing an organism's performance in anticipating changing environmental conditions. Therefore, it is important to understand the underlying mechanisms that connect the core pacemaker, which is located in the suprachiasmatic nuclei (SCN) of the hypothalamus, with peripheral organs. Several laboratories set out to identify genes that are under the influence of the circadian clock. It appears that the circadian clock coordinates transcription of key metabolic pathways thereby orchestrating the time course of physiological and behavioural processes. We review these investigations and put our experiments, the comparison of gene expression in SCN tissue of Per2 mutant and wild-type mice, in the context of these findings.

The Circadian Clock: A Manager of Biochemical Processes Within the Organism

ERRATUM: The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption

/pdf/erratum-the-clock-gene-per2-influences-the-glutamatergic-1uph8wzd9y.pdf

David Holzberg

Papers

The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption.

The Circadian Clock: A Manager of Biochemical Processes Within the Organism

Erratum: The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption (Nature Medicine (2005) 11 (35-42))