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2 - A clockwork web, Hastings M.H..doc

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McMaster University
David Rollo

Article#2: A Clockwork Web: Circadian Timing in Brain and Periphery, in Health and Disease • The hypothalamic suprachiasmatic nuclei (SCN) are our principal circadian oscillator – coordinates daily cycles of physiology and behaviour • local version of the SCN network are active in perpipheral, non neuronal tissues – regulate genes of circadian organization • wren – 4 humours – blood, cholic, melancholy, and phlegm • circadian rhythms are are daily cycles of physiology and behaviour that are driven by an oscillator with a period of approx one day o expression continues when person is isolated because the oscillator has a defined time Sleep and Wakening • day – catabolic processes to facilitate interaction with the world • night – anabolic processes – growth, repair and consolidation • evening – body temp drops and melatonin is produced to promote sleep • sleep onset – circadian secretion of growth hormone and prolactin • before dawn – adrenocortico-tropic axis prepares us for the physical and mental challenges of awakening • genotypes with circadian periods that match light and dark enjoy a fitness gain relative to individuals with faster or slower clocks – oppose internal temporal order – can lead to cardiovascular disease and cancer The SCN as our body clock • SCN – head ganglion of the circadian timing system • express in vitro circadian cycles • SCN can act as autonomous circadian clocks • neurons of SCN in dorsal “shell” are characterized by vasopressin expression and contain GABA • ventral “core” – neurons contain vasoactive intestinal polypeptide (VIP) • innervation of the dorsomedial hypothalamus contribute to circadian control of orexin/hypocretin systems which regulate wakefulness • rest/activity cycles – paracrine signaling: SCN releases growth factor α (TFGα) and prokineticin-2 (PK2) • in SCN GABA acts as a primary synchronizing signal among SCN neurons • VIP receptor subtype 2 (VPAC2) deficiency disrupts circadian activity/rest cycles • if balance between VIP, GABA and other signaling pathways is disrupted, the core oscillator is disabled Clock genes and circadian oscillation • 24 h oscillations sustained by – interlinked transcriptional and post-translational feedback loops in which complexes of the proteins products of the clock enter the nucleus and surpress transcription of their cognate genes o period (Pyr) and Cryptochrome (Cry) genes are negative components of the loop o Clock/Bmal1 heterodimers activate Cry and Per genes. Their products are the negative feedback loop, which causes gene expression suspension. o mutations of core clock genes alter stability, amplitude and/or period length of activity cycles, with altered circadian rythms of electrical firing in the SCN o familial advanced sleep syndrome (FASPA) – shortens circadian cycle by 2-4hrs Clock input and output • melanopsin – expressed in sub-population of retinal ganglion cells (RCGs) – projects directly to the SCN – mediates non-image forming photoreception • exposure to light suring circadian night increases the firing rates of SCN core neurons • after light exposure – core neurons show a sustained elevation of spike frequency, and electrical and/or paracrine signals spread to the SCN where further per induction occurs • prolonged light exposure  Cry is also induced • SCN adjustment – dusk light delays the loop by inducing Per as it spontaneiously falls, dawn light prematurely activates Per expression, advancing the clock • seasonal change in day length dawn and dusk are further apart  duration of Per expression lengthens Autonomous peripheral oscillators • mammalian clock genes are expressed rhythmically in peripheral tissue - local clocks are functional – autonomous, contain light sensitive circadian clocks, are assembled from the same gene products as the ‘master’ oscillator  expression lost in SCN lesioned animals • SCN is the sole origin of circadian structure • knocking out Per1, Cry1 or Cry 2 alters the circadian period of the cells, knocking out both Cry genes makes the cell arrhythmic • mammalian tissue clocks are not intrinsically light sensitive and rely on the SCN for indication of solar day • vasculature – complex in which Bmal1 dimerizes with either Clock of Npas2 drive circadian gene expression • peripheral tissues – Bmal2 is ecpressed in up to 9 tissue-specific isoforms, and dimerizes with Clock to drive CCGs • in periphery – clock genes peak 4-8 hrs later than in the SCN • liver – peak expression of Cry1 is even further delayed Tissue specific circadian programming • 5-9% of the transcriptome is under circadian control in the liver, with similar proportion in the heart and in the SCN • rhythmic groups are clustered into phase-typical groups  common phases reflect
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