Time-keeping System:Circadian Rhythms Helena Illnerová Institute of Physiology Academy of Sciences of the Czech Rep.
CIRCADIAN RHYTHMS • sleep-wake cycle • body temperature • behaviour • food and water intake • hormones • metabolism • body fluids • expression of genes
Subjective night Evening: sleepiness increases melatonin increases body temperature decreases Morning: cortisol increases melatonin decreases body temperature increases The subjective night is not necessarily equal to the real night
The outside period T = 24 h Entrainment: Tau* = 24 h Tau > 24 h: daily phase advance is necessary Tau < 24 h : daily phase delay is necessary
Light Entrainment • Light in the evening and in the first half of the night delays phase of the rhythms. • Light in the second half of the night and in the morning advances phase of the rhythms • Light during the subjective day does not change phase of the rhythms
THE PINEAL GLAND: SEROTONIN N-ACETYLTRANSFERASE N-ACETYLSEROTONIN HYDROXYINDOL-O-METHYL TRANSFERASE MELATONIN
DAY 0 DAY 1 TIME (h)
THE MAMMALIAN CLOCK GENES Clock BMal 1 (Mop 3), BMal 2 Per 1, Per 2 (Period) Cry 1, Cry 2 (Cryptochrome) Rev – Erb α CK1 Є CK1 δ (kasein kinase) CLOCK-CONTROLLED GENES Per 3 AVP (arginin vasopresin) Dbp (D-element binding protein)
translation PermRNA) protein product of the clock transcription modification ? DNA (gene Per) modified protein of the clock Protein transfer to the nucleus Clock-controlled genes Overt circadian rhythms + ++ +++ - DNA - - DNA - - DNA – + ++ +++
Are the clock genes responsible for CHRONOTYPES? Larks vs. owls?
Vision entrainment PHOTORECEPTORS retinal rods retinal ganglionic and cones cells PHOTOPIGMENT Rodopsin Melanopsin Optic nerves RHT, GHT Optic cortex SCN; ?
First, second and third messengers • GLUTAMATE • cAMP; cGMP; Ca ions; NO • C-FOS; pCREB; PER1; PER2
Hierarchy of the Circadian System S C N Light Melatonin NPY liver lungs kidney heart pancreas Restricted feeding Glucocorticoids
ENTRAINMENT OF THE TIME-KEEPING SYSTEM • Entainment of the SCN: by light • Entrainment of peripheral organs: • From SCN • By feeding • Via corticoids • ?
Peripheral organs as clocks - Oscillation in the organ culture • Different periods and phases • Oscillations persist even after the SCN lesion but become desynchronized • PERIPHERAL ORGANS ARE CLOCKS PER SE BUT SCN PLAYS THE COORDINATION AND SYNCHRONIZING ROLE
Expression of Genes About 10% of genes are expressed in a rhythmic way: • CLOCK GENES • CELL CYCLE GENES • GENES FOR APOPTOSIS • ORGAN SPECIFIC GENES
Partial hepatectomy Clocks of the cell cycle Circadian clocks Go BMAL 1 CLOCK G1 M CDC 25 hourglass CDC 2 CYCLIN B WEE 1 REV-ERBQ S G2 CRY 1, 2 PER 1, 2 Liver growth
TUMOUR GROWTH • PER2 Bmal1/Clock c Myc • PER2 p53 apoptosis • A WEAK CIRCADIAN SYSTEM
METABOLIC DISORDERS-OBESITY • In food intake (night eating syndrom) • In balance of rhythms of leptin, ghrelin, insulin (e.g., when sleep is insufficient ) • In loss of appetite (Clock mutant mice)
Disorders of the Circadian System • Free-run • DSPS • ASPS • Fragmentation of sleep • Higher risk for oncologic diseases • Metabolic disorders
CHRONOBIOLOGY Molecular Biology Neurobiology Ethology Internal Medicine Sports and Labour Medicine Psychology Psychiatry Neurology Oncology
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