Time-keeping System:Time-keeping System:Circadian RhythmsCircadian Rhythms

Helena IllnerováHelena IllnerováInstitute of PhysiologyInstitute of Physiology

Academy of Sciences of the Czech Rep.Academy of Sciences of the Czech Rep.

CIRCADIAN RHYTHMSCIRCADIAN RHYTHMS

sleep-wake cyclesleep-wake cycle body temperaturebody temperature behaviourbehaviour food and water intakefood and water intake hormones hormones metabolismmetabolism body fluidsbody fluids expression of genesexpression of genes

Subjective nightSubjective night

Evening:Evening: sleepiness increasessleepiness increasesmelatonin increasesmelatonin increasesbody temperature decreasesbody temperature decreases

Morning: Morning: cortisol increasescortisol increasesmelatonin decreasesmelatonin decreasesbody temperature increasesbody temperature increases

The subjective night is not The subjective night is not necessarily equal to the real night necessarily equal to the real night

Tau > 24 h: daily phase advance is necessary

Tau < 24 h : daily phase delay is necessary

The outside period T = 24 h

Entrainment: Tau* = 24 h

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-ACETYLSEROTONIN

MELATONIN

N-ACETYLTRANSFERASE

HYDROXYINDOL-O-METHYLTRANSFERASE

DAY 0 DAY 1

TIME (h)

THE MAMMALIAN CLOCK GENES

ClockBMal 1 (Mop 3), BMal 2Per 1, Per 2 (Period)Cry 1, Cry 2 (Cryptochrome)Rev – Erb αCK1 Є CK1 δ (kasein kinase)

CLOCK-CONTROLLED GENES

Per 3AVP (arginin vasopresin)Dbp (D-element binding protein)

translation

+ ++ +++- DNA - - DNA - - DNA – + ++ +++

Per mRNA)

protein product of the clock

modification ?transcription

DNA(gene Per)

modified proteinof the clock

Protein transfer to the nucleus

Clock-controlled genes

Overt circadian rhythms

Are the clock genes Are the clock genes responsible for responsible for CHRONOTYPES? CHRONOTYPES?

Larks vs. owls?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 First, second and third messengersmessengers

GLUTAMATEGLUTAMATE cAMP; cGMP; Ca ions; NOcAMP; cGMP; Ca ions; NO C-FOS; pCREB; PER1; PER2C-FOS; pCREB; PER1; PER2

Hierarchy of the Circadian System

S C NLightMelatoninNPY

Glucocorticoids

Restricted feeding

kidney heart pancreaslungsliver

ENTRAINMENT OF THE ENTRAINMENT OF THE TIME-KEEPING SYSTEMTIME-KEEPING SYSTEM

Entainment of the SCN: by lightEntainment of the SCN: by light Entrainment of peripheral Entrainment of peripheral

organs:organs:- From SCN From SCN - By feedingBy feeding- Via corticoidsVia 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 GenesExpression of Genes

About 10% of genes are About 10% of genes are expressed in a rhythmic way:expressed in a rhythmic way:

- CLOCK GENESCLOCK GENES- CELL CYCLE GENESCELL CYCLE GENES- GENES FOR APOPTOSISGENES FOR APOPTOSIS- ORGAN SPECIFIC GENESORGAN SPECIFIC GENES

Partial hepatectomy

hourglass

Go

G1

S

M

G2

Liver growth

Clocks ofthe cell cycle

Circadianclocks

CDC 2CYCLIN B

CDC 25

WEE 1

BMAL 1CLOCK

REV-ERBQ

CRY 1, 2PER 1, 2

TUMOUR GROWTH

• PER2 Bmal1/Clock c Myc

• PER2 p53 apoptosis

• A WEAK CIRCADIAN SYSTEM

METABOLIC DISORDERS-METABOLIC DISORDERS-OBESITYOBESITY

- In food intake (night eating In food intake (night eating syndrom)syndrom)

- In balance of rhythms of leptin, In balance of rhythms of leptin, ghrelin, insulin (e.g., when sleep ghrelin, insulin (e.g., when sleep is insufficient )is insufficient )

- In loss of appetite (Clock mutant In loss of appetite (Clock mutant mice)mice)

Disorders of the Circadian Disorders of the Circadian SystemSystem

Free-runFree-run DSPSDSPS ASPSASPS Fragmentation of sleepFragmentation of sleep Higher risk for oncologic Higher risk for oncologic

diseasesdiseases Metabolic disorders Metabolic disorders

CHRONOBIOLOGYCHRONOBIOLOGYMolecular Biology

Neurobiology

Ethology

Internal Medicine

Sports and Labour

Medicine

Psychology

Psychiatry

Neurology

Oncology

The wonder of the world,The wonder of the world,

the beauty and the power,the beauty and the power,

the shapes of things,the shapes of things,

their colour, lights and shades.their colour, lights and shades.

These I saw.These I saw.

Look ye also while life lasts.Look ye also while life lasts.