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Mammalian circadian

Jhenkruthi Vijaya Shankara, Angélique Orr, Richelle Mychasiuk, Michael C Antle
The mammalian circadian clock is synchronized to the day:night cycle by light. Serotonin modulates the circadian effects of light, with agonists inhibiting response to light and antagonists enhancing responses to light. A special class of serotonergic compounds, the mixed 5-HT1A agonist/antagonists, potentiate light-induced phase advances by up to 400% when administered acutely. In this study, we examine the effects of one of these mixed 5-HT1A agonist/antagonists, BMY7378, when administered chronically. Thirty adult male hamsters were administered either vehicle or BMY7378 via surgically implanted osmotic minipumps over a period of 28 days...
October 17, 2017: European Journal of Neuroscience
Oliver T Phillipson
The motor deficits which characterise the sporadic form of Parkinson's disease arise from age-related loss of a subset of dopamine neurons in the substantia nigra. Although motor symptoms respond to dopamine replacement therapies, the underlying disease process remains. This review details some features of the progressive molecular pathology and proposes deployment of a combination of nutrients: R-lipoic acid, acetyl-l-carnitine, ubiquinol, melatonin (or receptor agonists) and vitamin D3, with the collective potential to slow progression of these features...
October 3, 2017: Ageing Research Reviews
Lucia Y Du, Hannah Darroch, Pramuk Keerthisinghe, Elina Ashimbayeva, Jonathan W Astin, Kathryn E Crosier, Philip S Crosier, Guy Warman, James Cheeseman, Christopher J Hall
The circadian clock, which evolved to help organisms harmonize physiological responses to external conditions (such as the light/dark cycle, LD), is emerging as an important regulator of the immune response to infection. Gaining a complete understanding of how the circadian clock influences the immune cell response requires animal models that permit direct observation of these processes within an intact host. Here, we investigated the use of larval zebrafish, a powerful live imaging system, as a new model to study the impact of a fundamental zeitgeber, light, on the innate immune cell response to infection...
October 4, 2017: Scientific Reports
Laurence A Brown, John Williams, Lewis Taylor, Ross J Thomson, Patrick M Nolan, Russell G Foster, Stuart N Peirson
The master circadian pacemaker in mammals is located in the suprachiasmatic nuclei (SCN) which regulate physiology and behaviour, as well as coordinating peripheral clocks throughout the body. Investigating the function of the SCN has often focused on the identification of rhythmically expressed genes. However, not all genes critical for SCN function are rhythmically expressed. An alternative strategy is to characterize those genes that are selectively enriched in the SCN. Here, we examined the transcriptome of the SCN and whole brain (WB) of mice using meta-analysis of publicly deposited data across a range of microarray platforms and RNA-Seq data...
September 29, 2017: Nucleic Acids Research
Andreas Neueder, Theresa A Gipson, Sophie Batterton, Hayley J Lazell, Pamela P Farshim, Paolo Paganetti, David E Housman, Gillian P Bates
The heat shock response (HSR) is a mechanism to cope with proteotoxic stress by inducing the expression of molecular chaperones and other heat shock response genes. The HSR is evolutionarily well conserved and has been widely studied in bacteria, cell lines and lower eukaryotic model organisms. However, mechanistic insights into the HSR in higher eukaryotes, in particular in mammals, are limited. We have developed an in vivo heat shock protocol to analyze the HSR in mice and dissected heat shock factor 1 (HSF1)-dependent and -independent pathways...
October 2, 2017: Scientific Reports
Elliott Scott Milner, Michael Tri Hoang Do
Environmental illumination spans many log units of intensity and is tracked for essential functions that include regulation of the circadian clock, arousal state, and hormone levels. Little is known about the neural representation of light intensity and how it covers the necessary range. This question became accessible with the discovery of mammalian photoreceptors that are required for intensity-driven functions, the M1 ipRGCs. The spike outputs of M1s are thought to uniformly track intensity over a wide range...
September 27, 2017: Cell
Daniel J Felmlee, Dominic Grün, Thomas F Baumert
The liver is composed of approximately a million hepatic lobules, microscopic hexagonal units that are patterned together in a three dimensional vasculature. Blood filters from portal triad points into central vein points at the center of each hexagonal lobule (Fig. 1). The lobule consists of hepatocyte plates that carry a gradient of recently absorbed nutrients from the digestive tract, diminishing oxygen, and hormones and Wnt morphogens to form different metabolic zones that the hepatocytes occupy. This specialized structure partitions hepatic functions such as liver detoxification, dietary nutrient absorption, and lipid synthesis (1)...
September 27, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Shuo-Wen Chang, Toshinori Yoshihara, Shuichi Machida, Hisashi Naito
Intracellular signaling exhibits circadian variation in the suprachiasmatic nucleus and liver. However, it is unclear whether circadian regulation also extends to intracellular signaling pathways in the cardiac and skeletal muscles. Here, we examined circadian variation in the intracellular mammalian target of rapamycin (mTOR)/70 kDa ribosomal protein S6 kinase 1 (p70S6K) and extracellular signal-regulated kinase (ERK) pathways, which regulate protein synthesis in rat cardiac and skeletal muscles. Seven-week-old male Wistar rats were assigned to six groups: Zeitgeber time (ZT) 2, ZT6, ZT10, ZT14, ZT18, and ZT22 (ZT0, lights on; ZT12, lights off)...
March 2017: Biochemistry and Biophysics Reports
Virgine Laurent, Anamika Sengupta, Aída Sánchez-Bretaño, David Hicks, Gianluca Tosini
Earlier studies in Xenopus have indicated a role for melatonin in the regulation of retinal disk shedding, but the role of melatonin in the regulation of daily rhythm in mammalian disk shedding and phagocytosis is still unclear. We recently produced a series of transgenic mice lacking melatonin receptor type 1 (MT1) or type 2 (MT2) in a melatonin-proficient background and have shown that removal of MT1 and MT2 receptors induces significant effects on daily and circadian regulation of the electroretinogram as well as on the viability of photoreceptor cells during aging...
September 21, 2017: Experimental Eye Research
Shunsuke Tsuchiya, Ethan D Buhr, Tomomi Higashide, Kazuhisa Sugiyama, Russell N Van Gelder
PURPOSE: Intraocular pressure (IOP) is known to have a strong circadian rhythm, yet how light/dark cycles entrain this rhythm is unknown. The purpose of this study was to assess whether, like the retina, the mammalian ciliary body and IOP clocks have an intrinsic ability to entrain to light/dark cycles. METHODS: Iris-ciliary body complexes were obtained from period2:luciferase (PER2::LUC) mice and cultured to measure bioluminescence rhythmicity. Pairs of the iris-ciliary body complex were exposed to antiphasic 9:15 h light/dark cycle in vitro...
2017: PloS One
Peter J Mark, Rachael C Crew, Michaela D Wharfe, Brendan J Waddell
From the perspective of circadian biology, mammalian pregnancy presents an unusual biological scenario in which an entire circadian system (i.e., that of the fetus) is embodied within another (i.e., that of the mother). Moreover, both systems are likely to be influenced at their interface by a third player, the placenta. Successful pregnancy requires major adaptations in maternal physiology, many of which involve circadian changes that support the high metabolic demands of the growing fetus. A functional role for maternal circadian adaptations is implied by the effects of circadian disruption, which result in pregnancy complications including higher risks for miscarriage, preterm labor, and low birth weight...
September 1, 2017: Journal of Biological Rhythms
Gregory L Willis, Christopher B Freelance
The role of the circadian system in Parkinson's disease (PD) is a topic of increasing scientific interest. This has emerged from recent studies demonstrating an altered response of PD patients to treatment in relation to the phase of the light/dark cycle and from other work defining the functional significance of melanocytes in PD: a cell type that the nigro-striatal dopamine (NSD) system and circadian system both contain. The present study was undertaken to determine the sensitivity of the pineal, as the final common pathway of the circadian system, to light delivered directly to the pineal via surgical implantation of LEDs...
September 15, 2017: Physiology & Behavior
Alexander C West, Laura Smith, David W Ray, Andrew S I Loudon, Timothy M Brown, David A Bechtold
Most organisms use internal biological clocks to match behavioural and physiological processes to specific phases of the day-night cycle. Central to this is the synchronisation of internal processes across multiple organ systems. Environmental desynchrony (e.g. shift work) profoundly impacts human health, increasing cardiovascular disease and diabetes risk, yet the underlying mechanisms remain unclear. Here, we characterise the impact of desynchrony between the internal clock and the external light-dark (LD) cycle on mammalian physiology...
September 12, 2017: Nature Communications
Rajindra P Aryal, Pieter Bas Kwak, Alfred G Tamayo, Michael Gebert, Po-Lin Chiu, Thomas Walz, Charles J Weitz
The mammalian circadian clock is built on a feedback loop in which PER and CRY proteins repress their own transcription. We found that in mouse liver nuclei all three PERs, both CRYs, and Casein Kinase-1δ (CK1δ) are present together in an ∼1.9-MDa repressor assembly that quantitatively incorporates its CLOCK-BMAL1 transcription factor target. Prior to incorporation, CLOCK-BMAL1 exists in an ∼750-kDa complex. Single-particle electron microscopy (EM) revealed nuclear PER complexes purified from mouse liver to be quasi-spherical ∼40-nm structures...
September 7, 2017: Molecular Cell
Ueli Schibler
In this issue of Molecular Cell, two papers address the biochemical structure of a large protein complex containing components of the mammalian circadian clock (Aryal et al., 2017) and a mechanism rendering this molecular timekeeper temperature-compensated (Shinohara et al., 2017).
September 7, 2017: Molecular Cell
Xue Liang, Garret A FitzGerald
The mammalian circadian clock system, which includes the master clock and peripheral clocks, times different biological processes in reaction to external cues, such as the light-dark cycle. However, the chronobiology of prokaryotic cells is less well understood, except for in cyanobacteria. The recent blooming of gut microbiome research has revealed a critical role for the trillions of microbes residing in the vertebrate gut in determining both health and disease in the host. The question of whether the gut microbiome exhibits circadian oscillation and how it synchronizes with the host circadian clock has attracted considerable interest...
August 1, 2017: Journal of Biological Rhythms
Antero Salminen, Kai Kaarniranta, Anu Kauppinen
FGF21 is a multifunctional metabolic and stress hormone which is normally expressed in liver but cellular stress, e.g. mitochondrial or endoplasmic reticulum (ER) stress, can induce its expression and subsequent secretion from several mammalian tissues. The stress kinases of the integrated stress response (ISR) pathway stimulate the expression of FGF21 through the activation of ATF4 transcription factor, thus enhancing cellular stress resistance. The metabolic and stress-inducible transactivation mechanisms of FGF21 gene are mostly mediated through separate pathways...
August 24, 2017: Cellular Signalling
Takako Noguchi, Tanya L Leise, Nathaniel J Kingsbury, Tanja Diemer, Lexie L Wang, Michael A Henson, David K Welsh
Circadian rhythms of mammalian physiology and behavior are coordinated by the suprachiasmatic nucleus (SCN) in the hypothalamus. Within SCN neurons, various aspects of cell physiology exhibit circadian oscillations, including circadian clock gene expression, levels of intracellular Ca(2+) ([Ca(2+)]i), and neuronal firing rate. [Ca(2+)]i oscillates in SCN neurons even in the absence of neuronal firing. To determine the causal relationship between circadian clock gene expression and [Ca(2+)]i rhythms in the SCN, as well as the SCN neuronal network dependence of [Ca(2+)]i rhythms, we introduced GCaMP3, a genetically encoded fluorescent Ca(2+) indicator, into SCN neurons from PER2::LUC knock-in reporter mice...
July 2017: ENeuro
Yasuhiro Umemura, Nobuya Koike, Munehiro Ohashi, Yoshiki Tsuchiya, Qing Jun Meng, Yoichi Minami, Masayuki Hara, Moe Hisatomi, Kazuhiro Yagita
Circadian clock oscillation emerges in mouse embryo in the later developmental stages. Although circadian clock development is closely correlated with cellular differentiation, the mechanisms of its emergence during mammalian development are not well understood. Here, we demonstrate an essential role of the posttranscriptional regulation of Clock subsequent to the cellular differentiation for the emergence of circadian clock oscillation in mouse fetal hearts and mouse embryonic stem cells (ESCs). In mouse fetal hearts, no apparent oscillation of cell-autonomous molecular clock was detectable around E10, whereas oscillation was clearly visible in E18 hearts...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
Ritsuko Matsumura, Makoto Akashi
Cell-autonomous oscillation in clock gene expression drives circadian rhythms. The development of comprehensive analytical techniques, such as bioinformatics and ChIP-sequencing, has enabled the genome-wide identification of potential circadian transcriptional elements that regulate the transcriptional oscillation of clock genes. However, detailed analyses using traditional biochemical and molecular-biological approaches, such as binding and reporter assays, are still necessary to determine whether these potential circadian transcriptional elements are actually functional and how significantly they contribute to driving transcriptional oscillation...
September 29, 2017: Journal of Biological Chemistry
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