Directeur de recherche : Dr Howard Cooper

Directeur de l’équipe : Dr Howard COOPER

Intitulé de l’équipe : Département de Chronobiologie
Rattachement (EPST, INSERM, CNRS) : Inserm, Université Lyon 1
Adresse de l’équipe de recherche : Inserm U846, Institut Cellule Souche et Cerveau, 18 avenue du Doyen Lépine, F-69500 Bron
Site internet :

Mots clefs : Rythmicité circadienne, cycle veille-sommeil, photoréception non-visuelle, mélanopsine, sensibilité à la lumière.

Thèmes de recherche :

*Deciphering the role of the novel photopigment Melanopsin in the synchronisation of central and retinal clocks in animals and humans.
*Effects of age and ocular pathologies on the circadian timing and sleep
*Optimization of light exposure strategies to optimize synchronisation of the human circadian timing system

Contexte scientifique :
Light exerts profound influences on human circadian rhythms and sleep, that in contrast ti vision are mediated by a unique pathway comprised of ganglion cells expressing melanopsin, an invertebrate-like photopigment discovered in the retina of mammals and humans only 10 years ago. This melanopsin pathway regulates circadian rhythms, the sleep wake cycle and other non-visual responses (hormone synthesis, pupil responses, alertness, cognition, cardiovascular activity The transfer of information to clinical (diagnostic tools, light therapy of chronobiological disorders including sleep disorders and seasonal affective disorders, cell therapy) and industrial (lighting technology) applications is progressing rapidly. Our team is a major actor in this domain and the only laboratory to combine molecular, cellular, and physiological approaches in models ranging from in vitro cell culture to in vivo transgenic mice, non-human and human primates.

Our overall goal is to understand the basic mechanisms of non-visual photoreception and the effects of light on clock genes and physiology in normal and pathological states. We investigate in animal models (rodent, primate) and in humans the roles of rods, cones and melanopsin in shaping the photic message that is transmitted to the brain. We apply innovative modelling techniques to derive the contributions of different photoreceptors from various response assays. To validate these models, we use spectral light stimulation in normal and photoreceptor deficient mice, as clinical models of human retinal pathologies, and investigate alterations in the responses of opsin genes, clock genes, physiology and behavior. The hypotheses and experimental strategies that emerge from these studies are carried over to investigations in humans (Human Chronobiology Facility, HCL) to assess the influence of circadian photoreception on normal physiology (hormones, alertness, sleep) and alterations due to age or retinal pathologies (glaucoma, retinitis pigmentosa).

Projet en cours :

Description of melanopsin response properties and pathways in the primates and humans
Leader : HM COOPER (howard.cooper[a]
Co-Investigators : C Gronfier, O Dkhissi-Benyahya, A. Nicolas, G Gingras
The response properties of the melanopsin photopigment signalling system witll be explored using assays of light suppression of melatonin secretion, pupillary reflex, electrophysiology and fMRI. Effects of invalidation of melanopsin (siRNA, antagonists) on light responses, entrainment of circadian rhythms and sleep will be investigated. Optogenetic techniques using targeted gene transfer of fluorescent probes in melanopsin cells will be used to trace input pathways to the brain.

Impact of photoreceptor alteration on the functioning and synchronization of retinal and central clocks
Leader : O DKHISSI-BENYAHYA (ouria.benyahya[a]
Co-Investigators : HM Cooper, C Gronfier, A. Nicolas, G Gingras, L.Canaple (E.N.S., Lyon)
The retina of mammals contains an autonomous circadian oscillator at the origin of many cellular, and physiological processes. Although these events are critical for retinal functions, it remain unclear how the mammalian retinal circadian clock controls ocular and central physiological rhythmicity. Whether the absence of a specific photoreceptor (melanopsin-expressing ganglion cells) can contribute to dysfunction of the retinal and/or the central clocks will be evaluated using in vivo (anatomical, molecular, cellular and behavioural) and in vitro (real time bioluminescence) approaches in several mouse models : mouse knockout for the melanopin gene (Opn4-/-) and transgenic mouse caring a clock reporter system (Opn4-/- ; rev-erb-luciferase and Per1-luciferase). Deliverable. Publication in international journal (M60)

The role of light in the synchronization of human circadian rhythms and sleep. Effects of age and retinal pathologies.
Leader : C GRONFIER (claude.gronfier[a]
Co-Investigators :, HM Cooper, O Dkhissi-Benyahya, R Najjar, A. Nicolas, G Gingras
The effects of aging and retinal pathologies on the synchronization of human circadian rhythms and sleep will be investigated in humans. Non visual responses to light will be explored at the endocrinological level (melatonin and cortisol secretion), the electrophysiological level (pupillary light reflex, electroencephalography, electrocardiography), the behavioural level (sleep-wake cycle, actigraphy), and at the cognitive level (neurobehavioral tasks).

Publications (2007-2011)

1. Nicolas A (2007) Dépression et sommeil : aspects cliniques et polysomnographiques. European Psychiatry, 22 :13-18
2. Dkhissi-Benyahya O, Gronfier C, De Vanssay W, Flamant F, Cooper HM (2007) Modelling the role of mid-wavelength cones in circadian responses to light. Neuron, 53:677-87.
3. Gronfier C, Wright KP, Jewett ME, Kronauer RE, Czeisler CA (2007) Entrainment of the human circadian timing system to longer-than-24 h days. Proc Natl Acad Sci U S A. 104(21):9081-6.
4. Mure LS, Rieux C, Hattar S, Cooper HM (2007) Restoration and enhancement of melanopsin-dependent non-visual responses by light : evidence for photopigment bistability in vivo. J Biol Rhythms 22(5) : 411-424.
5. Chiquet C, Lina G, Benito Y, Cornut PL, Etienne J, Romanet JP, Denis P, Vandenesch F (2007) Polymerase chain reaction identification in aqueous humor of patients with postoperative endophthalmitis. J Cataract Refract Surg. 635-41.
6. St. Hilaire M, Gronfier C, Zeitzer JM, Klerman EB (2007) A physiologically-based mathematical model of melatonin including ocular light suppression and interactions with the circadian pacemaker. J Pineal Res. 43(3):294-304.
7. Chiquet C, Cornut PL, Vinh V, Maurin M, Romanet JP (2007) Acute endophthalmitis : from bacteria to clinical settings. J Fr Ophtalmol. 30(10):1060-6.
8. Drouyer E, Rieux C, Hut RA, Cooper HM (2007) Responses of SCN neurons to light and dark adaptation : relative contributions of melanopsin and rod-cone inputs. J Neurosci. 27(36) : 9623-9631.
9. Claustrat B, Valatx JL, Harthé C, Brun J. Effect of constant light on prolactin and corticosterone rhythms evaluated using a noninvasive urine sampling protocol in the rat. Horm Metab Res. 2008 Jun ;40(6):398-403. Epub 2008 Apr 14.
10. Fevre-Montange M, Champier J, Szathmari A, Brisson C, Reboul A, Mottolese C, Fauchon F, Claustrat B, Jouvet A. Histological features and expression of enzymes implicated in melatonin synthesis in pineal parenchymal tumours and in cultured tumoural pineal cells. Neuropathol Appl Neurobiol. 2008 Jun ;34(3):296-305. Epub 2007 Oct 29.
11. Quilici S, Abrams KR, Nicolas A, Martin M, Petit C, Lleu PL, Finnern HW (2008) Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome. Sleep Medecine, 9 : 715-26
12. Denis P, Le Pen C, Umuhire D, Berdeaux G (2008). Treatment carryover impacts on effectiveness of intraocular pressure lowering agents, estimated by a discrete event simulation model. Eur J Ophthalmol. 18, 44-51
13. Hut RA, Oklejewicz M, Rieux C, Cooper HM (2008) Photic sensitivity ranges of hamster pupillary and circadian phase responses do not overlap. J Biol Rhythms 23 : 37-48.
14. Cooper HM, Mure LS (2008) Expected and Unexpected Properties of Melanopsin Signalling. J Biol Rhythms. 23(5):392-393.
15. Cornut PL, Français-Maury C, Mauget-Faÿsse M (2008) Macular edema from various etiologies. J Fr Ophtalmol. 31(2):225-33.
16. Français-Maury C, Cornut PL, Mauget-Faÿsse M (2008) Examination of vitreomacular traction syndrome. J Fr Ophtalmol. 31(2):187-91.
17. Chiquet C, Cornut PL, Benito Y, Thuret G, Maurin M, Lafontaine PO, Pechinot A, Palombi K, Lina G, Bron A, Denis P, Carricajo A, Creuzot C, Romanet JP, Vandenesch F ; French Institutional Endophthalmitis Study Group (2008) Eubacterial PCR for bacterial detection and identification in 100 acute postcataract surgery endophthalmitis. Invest Ophthalmol Vis Sci. 49(5):1971-8.
18. Jeffery G, Levitt J, Cooper HM (2007) Segregated hemispheric pathways through the optic chiasm distinguishes primates from rodents. Neuroscience, 2 ;157(3):637-43.
19. Drouyer E, Dkhissi-Benyahya O, Chiquet C, Woldemussie E, Ruiz G, Wheeler LA, Denis P, Cooper HM (2008) Glaucoma alters the circadian timing system. PLoSONE 3(12) : e3931.
20. Cornut PL, Chiquet C, Bron A, Romanet JP, Lina G, Lafontaine PO, Benito Y, Pechinot A, Burillon C, Vandenesch F, Denis P (2008) Microbiological identification of bleb-related delayed-onset endophthalmitis caused by moraxella species. Journal of Glaucoma. 17(7):541-5.
21. Pérignon S, Cornut PL, Boyer F, Janin-Magnificat H, Burillon C, Denis P (2008) Bilateral oedipism : a case report. J Fr Ophtalmol. 31(6):614-7.
22. Cornut PL, Chiquet C (2008) Intravitreal injection of antibiotics in endophthalmitis. J Fr Ophtalmol. 31(8):815-23.
23. Ritzenthaler T, Nighoghossian N, Berthiller J, Schott AM, Cho TH, Derex L, Brun J, Trouillas P, Claustrat B. Nocturnal urine melatonin and 6-sulphatoxymelatonin excretion at the acute stage of ischaemic stroke. J Pineal Res. 2009 Apr ;46(3):349-52.
24. Szulc P, Claustrat B, Delmas PD. Serum concentrations of 17beta-E2 and 25-hydroxycholecalciferol (25OHD) in relation to all-cause mortality in older men—the MINOS study. Clin Endocrinol (Oxf). 2009 Oct ;71(4):594-602. Epub 2009 Jan 22.
25. Leston J, Mottolese C, Champier J, Jouvet A, Brun J, Sindou M, Chazot G, Claustrat B, Fèvre-Montange M. Contribution of the daily melatonin profile to diagnosis of tumors of the pineal region. J Neurooncol. 2009 Jul ;93(3):387-94. Epub 2009 Jan 25.
26. Aptel F, Masset H, Burillon C, Robin A, Denis P (2009). The influence of disease severity on quality of eye-drop administration in patients with glaucoma or ocular hypertension. Br J Ophthalmol 93:700-1
27. Mure LS, Cornut PL, Rieux C, Drouyer E, Gronfier C, Denis P, Cooper HM (2009) Melanopsin bistabiliy : A fly’s eye technology in the human retina. PLoS One. 4(6):e5991.
28. Lukáts A, Berta A, Földesi D, Hajós A, Cooper HM, Bennett HM, Szabó A, Röhlich P, Szél A (2009) Dual cones in the peripheral retina of diurnal rodents : a possible site for photoreceptor regeneration. (Invest. Ophthal. Vis Sci., in press)
29. Renard E, Palombi K, Gronfier C, Pepin JL, Noel C, Chiquet C, Romanet JP. 24-hour (nyctohemeral) rhythm of intraocular pressure and ocular perfusion pressure in normal tension glaucoma patients. Invest Ophthalmol Vis Sci. 2010 Feb ;51(2):882-9.
30. Dollet A, Albrecht U, Cooper HM, Dkhissi-Benyahya O (2009) Cones are required for short duration responses of the circadian system to light (submitted, J Neurosci)
31. Oosthuizen MK, Bennett NC, Cooper HM. Photic induction of Fos in the suprachiasmatic nucleus of African mole-rats : responses to increasing irradiance. Chronobiol Int. 2010 Sep ;27(8):1532-45.
32. Cornu C, Remontet L, Noel-Baron F, Nicolas A, Feugier-Favier N, Roy P, Claustrat B, Saadatian-Elahi M, Kassaï B. A dietary supplement to improve the quality of sleep : a randomized placebo controlled trial. BMC Complement Altern Med. 2010 Jun 22 ;10:29.
33. Pina G, Brun J, Tissot S, Claustrat B. Long-term alteration of daily melatonin, 6-sulfatoxymelatonin, cortisol, and temperature profiles in burn patients : a preliminary report. Chronobiol Int. 2010 Jan ;27(2):378-92.
34. Leston J, Harthé C, Brun J, Mottolese C, Mertens P, Sindou M, Claustrat B. Melatonin is released in the third ventricle in humans. A study in movement disorders. Neurosci Lett. 2010 Jan 29 ;469(3):294-7. Epub 2009 Dec 11
35. Claustrat B, Brun J, Borson-Chazot F, Cohen-Tannoudji D, Claustrat F, Julien J, Lemoine P. Suppression of melatonin secretion in healthy subjects with eyeglass LED delivery system. Neuro Endocrinol Lett. 2010 ;31(3):330-5.
36. El Moussaouiti R, Bouhaddou N, Sabbar M, Cooper HM, Lakhdar-Ghazal N. Phase and period responses of the jerboa Jaculus orientalis to short light pulses. Chronobiol Int. 2010 Aug ;27(7):1348-64.
37. Dollet A, Albrecht U, Cooper HM, Dkhissi-Benyahya O. Cones are required for normal temporal responses to light of phase shifts and clock gene expression. Chronobiol Int. 2010 Jun ;27(4):768-81.
38. Quera-Salva MA, Hartley S, Claustrat B, Brugiéres L. Circadian rhythm disturbances associated with psychiatric symptoms in a patient with a pineal region tumor. Am J Psychiatry. 2011 Jan ;168(1):99-100.
39. Guénolé F, Godbout R, Nicolas A, Franco P, Claustrat B, Baleyte JM. Melatonin for disordered sleep in individuals with autism spectrum disorders : Systematic review and discussion. Sleep Med Rev. 2011 Mar 8. [Epub ahead of print]
40. Duffy JF, Cain SW, Chang AM, Phillips AJK, Munch MY, Gronfier C, Wyatt JK, Dijk D-J, Wright JP, Czeisler CA. Sex difference in intrinsic circadian period in humans. Proc Natl Acad Sci U S A, DOI:10.1073, May 2, 2011

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