Light and the circadian clock : effects on human health Claude Gronfier, Ph.D. Département de Chronobiologie Inserm 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
Fundamental Properties of the circadian pacemaker 2-resetting/entrainment by light 3- appropriately timed biological rhythms 1- endogenous self-sustained rhythm of approximately 24h Adapted from Hastings MH Nature Rev Neurosci 2003 Principles of human circadian entrainment 1- the endogenous period of the clock is not exactely 24 h
Timing of Sleep Episodes while living in a Cave 1 10 Consecutive Days in Cave 20 30 40 50 τ = 24.5 hrs Cave enthusiast Michel Siffre 1962 for 62 days in a cave in the French Alps no light, except his headlamp 0 C 120 m deep 8 16 24 8 16 24 8 16 Time of Day (h) Modified from Siffre, 1964 Endogenous circadian period in humans 11 10 9 Young adults (20-41 yr) 52 subjects (46M,6F) 24.11 ± 0.21 (SD) h Median = 24.15 h 8 Number of subjects 7 6 5 4 3 2 1 0 23.5 23.6 23.7 23.8 23.9 24.0 24.1 24.2 24.3 24.4 24.5 Intrinsic Circadian Period (τ ^ t ) 24.6 Gronfier C and Czeisler CA, unpublished
Endogenous circadian period and phase angle Night Owls Early birds Gronfier et al. PNAS May 22 2007 Principles of human circadian entrainment 2- the circadian clock is reset (daily) by light
Time-dependent direction of phase resetting End day / begining night => Phase delay the clock End night / begining day => Phase advance the clock Intensity-dependent clock resetting Zeitzer JM et al. 2000
3 Why is entrainment important? Because timing is everything! Fonctions contrôlées par l horloge biologique Syst. Nerveux Autonome performances cognitives humeur Thalamus activité motrice sommeil Cortex mémoiremoire lumière Glande pinéale Mélatonine Hypothalamus PVN HORLOGE CENTRALE NSC Tronc cérébral horloges périphp riphériquesriques hormones cycle cellulaire
Functionning at an inapropriate circadian time leads to andthis (nuclear power plant - Three Miles Island, USA, 4 am)
or this (explosion nuclear power plant - Tchernobyl, former-ussr, 1h23 am) Chronobiological Disorders (genetic component) - 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
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 th circadian clock LIGHT IS GOOD FOR YOU!
A NEW PHOTOPIGMENT IN THE HUMAN RETINA Colloque "Éclairage et Santé", Paris, 7 juin 2007 Howard M. Cooper, Claude Gronfier INSERM U846 Stem Cell and Brain Research Institute, Department of Chronobiology, Lyon CLASSICAL STRUCTURE OF THE RETINA RODS low light vision CONES (red, green, blue) LOSS bright OF light, VISION color vision? OUTER RETINA Light detection INNER RETINA Output to visual structures of the brain
Visual deficits in the absence of all rods and cones : Complete loss of visual perception Conservation of : Light synchronization of daily (circadian) rhythms Pupil reflexes Light suppression of the pineal hormone melatonin Blind mice lacking rods and cones (retinal degeneration, transgenically engineered) Blind Humans without conscious vision (intact eyes) non-rod non-cone retinal photopigment? MELANOPSIN IS EXPRESSED IN GANGLION CELLS AND CONE PHOTORECEPTORS IN HUMAN RETINA
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
MELANOPSIN IS SENSITIVE TO SHORT WAVELENGTH BLUE LIGHT MEL 480 nm MELANOPSIN RESPONDS TO VERY HIGH LIGHT LEVELS Dacey DM et al. Nature 2005
INTRINSIIC LIGHT RESPONSE PROPERTIES OF MELANOPSIN 1- SLOW TO RESPOND TO LIGHT ONSET 2- MAINTAIN THEIR RESPONSE TO LIGHT 3- CONTINUE TO RESPOND AFTER LIGHT OFFSET Rods/cones : Rapid phasic responses Melanopsin : Sustained Persistent responses LIGHT LIGHT TRANSDUCTION IN PHOTORECEPTORS Rods Cones Melanopsin i Light inactivates the photopigment (bleaching) λ 1 λ 1 11-cis LOSS OF SENSITIVITY TO LIGHT all trans phototransduction cascade phototransduction cascade Light response
CHROMOPHORE REGENERATION ciliary rhabdomeric λ 1 11-cis λ 1 light light independant regeneration regeneration photoregeneration photoisomerase all trans photosensory RPE or muller cells λ 2 light independent extrinsic to photoreceptor BISTABILITY light dependent intrinsic Light to depenent photoreceptor FUNCTIONAL ROLES OF MELANOPSIN IN NON-VISUAL FUNCTIONS Synchronisation of circadian rhythms Regulation of the sleep wake cycle Control of the pupillary reflex Seasonal reproduction Mood Autonomic control of thermo-regulation and heart rate
POSSIBLE INFLUENCE OF MELANOPSIN ON VISUAL FUNCTIONS 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 VISUAL AND NON-VISUAL RETINAL PATHWAYS Geniculate Nucleus Visual Cortex Superior Colliculus PERCEPTUAL VISION OPN Habenula IGL NON-VISUAL RESPONSES TO LIGHT Olfactory Tubercule Preoptic SCN LH, RCh Circadian Rhythms Sleep wake cycle Pupillary Reflex Seasonal Reproduction Mood Alertness Acute heart rate
CONCLUSION A fly s eye technology in the human retina One eye sees, the other feels (Paul Klee) Plate-forme de Recherche en Chronobiologie European Affiliated Centre for Human Chronobiology RESPONSABLES : Pr P. Denis, Dr C. Chiquet (Service d Ophtalmologie, HEH) Dr H.M. Cooper, Dr C. Gronfier (INSERM U371) Agrément HCL # 2207 S - CCPPRB RBM 0060022