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Light and the circadian clock : effects on human health

Claude Gronfier, Ph.D.

Département de ChronobiologieInserm U846, Institut Cellule Souche et Cerveau

Lyon, France

Colloque “Eclairage et Santé”Association Francaise de l’Eclairage (AFE) & Comité National Francais de l’Eclairage (CNFE)

Paris, 7 juin 2007

Localisation de l’horloge biologique (circadienne)

Suprachiasmatic Nucleus (nuclei) - SCN

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Adapted from Hastings MH Nature Rev Neurosci 2003

1- endogenous self-sustained rhythm of approximately 24h

2-resetting/entrainment by light

3- appropriately timedbiological rhythms

Fundamental Properties of the circadian pacemaker

Principles of human circadianentrainment

1- the endogenous period of theclock is not exactely 24 h

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Timing of Sleep Episodes while living in a Cave

Con

secu

tive

Day

s in

Cav

e

1

10

20

30

40

50

8 16 24 8 16 24 8 16Time of Day (h)

Cave enthusiast Michel Siffre1962 for 62 days in a cave in the French Alpsno light, except his headlamp0° C120 m deep

τ = 24.5 hrs

Modified from Siffre, 1964

23.5 23.6 23.7 23.8 23.9 24.0 24.1 24.2 24.3 24.4 24.50

1

2

3

4

5

6

7

8

9

10

11

Num

ber o

f sub

ject

s

Young adults (20-41 yr)52 subjects (46M,6F)24.11 ± 0.21 (SD) hMedian = 24.15 h

Intrinsic Circadian Period (τt) ^Intrinsic Circadian Period (τt) ^

Endogenous circadian period in humans

24.6

Gronfier C and Czeisler CA, unpublished

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Gronfier et al. PNAS May 22 2007

Endogenous circadian period and phase angle

Early birds

Night Owls

Principles of human circadianentrainment

2- the circadian clock is reset (daily) by light

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TimeTime--dependentdependent direction direction ofof phase phase resettingresetting

End day / begining night=> Phase delay the clock

End night / begining day=> Phase advance the clock

Zeitzer JM et al. 2000

IntensityIntensity--dependentdependent clockclock resettingresetting

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3 – Why is entrainment important?

Because timing is everything!

lumière

Hypothalamus

HORLOGE CENTRALENSC

Glande pinéaleMélatonine

Tronc cérébral

Cortex

Thalamus

PVN

sommeilsommeil

activitactivitéé motricemotriceSyst. Nerveux AutonomeSyst. Nerveux Autonome

performances cognitivesperformances cognitiveshumeurhumeur

mméémoiremoire

hormoneshormones

horloges phorloges péériphriphéériquesriques

cycle cellulairecycle cellulaire

Fonctions contrôlées par l’horloge biologique

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Functionning at an inapropriate circadian time leads to …

… and this …(nuclear power plant - Three Miles Island, USA, 4 am)

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… or this …(explosion nuclear power plant - Tchernobyl, former-USSR, 1h23 am)

- Advance Sleep Phase Syndrome (ASPS)- Delayed Sleep Phase Syndrome (DSPS)

- Free-running rhythm (blind and sighted)

- Seasonal (SAD) and non-seasonal depression

- Alzheimer’s disease

- Cancer

- Shift-work

- Jet-lag (transmeridian flight)

- Aging, ocular pathologies

Chronobiological Disorders(genetic component)

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Conclusion

1.Appropriate functioning requires appropriate circadian synchronization

2. Inappropriate circadian synchronization has consequences on sleep, cognitive perofrmance, metabolism

3.Chronic circadian resynchronization can lead to pathologies

4.Light can be used as a tool to synchronize thcircadian clock

LIGHT IS GOOD FOR YOU !

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INSERM U846 “Stem Cell and Brain Research Institute ”, Department of Chronobiology , Lyon

Colloque "Éclairage et Santé", Paris, 7 juin 2007

Howard M. Cooper, Claude Gronfier

A NEW PHOTOPIGMENT IN THE HUMAN RETINA

CLASSICAL STRUCTURE OF THE RETINA

OUTER RETINALight detection

INNER RETINAOutput to visual

structures of the brain

RODSlow light vision

CONES (red, green, blue)bright light, color visionLOSS OF VISION ?

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non-rod non-cone retinal photopigment ?

Blind mice lacking rods and cones (retinal degeneration, transgenically engineered)

Blind Humans without conscious vision (intact eyes)

Visual deficits in the absence of all rods and cones :

Complete loss of visual perception

Conservation of :Light synchronization of daily (circadian) rhythmsPupil reflexes Light suppression of the pineal hormone melatonin

MELANOPSIN IS EXPRESSED IN GANGLION CELLS AND CONE PHOTORECEPTORS IN HUMAN RETINA

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MELANOPSIN EXPRESSING RETINAL GANGLION CELLS FORM A « PHOTORECEPTIVE NET »

FUNCTIONAL ROLE OF MELANOPSIN ?

Melanopsin responses to light

Invertebrate-like Bistable photopigment

Functional roles of melanopsin in visual and non-visual light detection

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MEL 480 nm

MELANOPSIN IS SENSITIVE TO SHORT WAVELENGTH BLUE LIGHT

MELANOPSIN RESPONDS TO VERY HIGH MELANOPSIN RESPONDS TO VERY HIGH LIGHT LEVELSLIGHT LEVELS

Dacey DM et al. Nature 2005

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INTRINSIIC LIGHT RESPONSE INTRINSIIC LIGHT RESPONSE PROPERTIES OF MELANOPSIN PROPERTIES OF MELANOPSIN

1- SLOW TO RESPOND TO LIGHT ONSET2- MAINTAIN THEIR RESPONSE TO LIGHT3- CONTINUE TO RESPOND AFTER LIGHT OFFSET

LIGHT

Rods/cones :Rapid phasic responses

Melanopsin :Sustained

Persistent responses

i

1λ1 λ

phototransductioncascade

phototransductioncascade

all trans

11-cis

LIGHT TRANSDUCTION IN PHOTORECEPTORS

Light response

Rods – Cones Melanopsin

Light inactivatesthe

photopigment

(bleaching)

LOSS OF SENSITIVITY TO

LIGHT

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light independentextrinsic to photoreceptor

light dependentintrinsic to photoreceptor

light independantregeneration

CHROMOPHORE REGENERATION

λ2

photoregeneration

rhabdomeric

λ1

light independantregeneration

RPE or muller cells

ciliary

λ1

all trans

11-cis

λ2

rhabdomeric

λ1

photoisomerasephotosensory

BISTABILITYLight depenent

FUNCTIONAL ROLES OF MELANOPSIN IN NON-VISUAL FUNCTIONS

Synchronisation of circadian rhythmsRegulation of the sleep wake cycleControl of the pupillary reflexSeasonal reproductionMoodAutonomic control of thermo-regulation and heart rate

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Luminance coding (conscious perception of brightness?)

Changes in alertness to sensory stimuli

Modulation of a large-scale network of cortical areas involved in attention processes

POSSIBLE INFLUENCE OF MELANOPSIN ON VISUAL FUNCTIONS

VISUAL AND NON-VISUAL RETINAL PATHWAYS

Circadian RhythmsSleep wake cyclePupillary ReflexSeasonal ReproductionMood

AlertnessAcute heart rate

SCN

Geniculate NucleusVisual Cortex PERCEPTUAL

VISIONSuperiorColliculus

NON-VISUALRESPONSES

TO LIGHT

Preoptic

OlfactoryTubercule

Habenula

IGL

OPN

LH, RCh

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CONCLUSION

A fly’s eye technology in the human retina

“One eye sees, the other feels” (Paul Klee)

P RC

late-forme de echercheen hronobiologie

European Affi liated Centre for Human Chronobiology

Pr P. Denis, Dr C. Chiquet (Service d’Ophtalmologie, HEH) Dr H.M. Cooper, Dr C. Gronfier (INSERM U371)

RESPONSABLES :

Agrément HCL # 2207 S - CCPPRB RBM 0060022

European Affiliated Centre for Human Chronobiology