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

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-METHYL

TRANSFERASE

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

+ ++ +++

- DNA - - DNA - - DNA –

+ ++ +++

Per mRNA)

protein product of the clock

modification ? transcription

DNA (gene Per)

modified protein

of the clock

Protein transfer to the nucleus

Clock-controlled genes

Overt circadian rhythms

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

Glucocorticoids

Restricted feeding

kidney heart pancreas lungs liver

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

hourglass

Go

G1

S

M

G2

Liver growth

Clocks of

the cell cycle Circadian

clocks

CDC 2

CYCLIN B

CDC 25

WEE 1

BMAL 1

CLOCK

REV-ERBQ

CRY 1, 2

PER 1, 2

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

The wonder of the world,

the beauty and the power,

the shapes of things,

their colour, lights and shades.

These I saw.

Look ye also while life lasts.