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Sleep homeostasis is in the eyes !

Research unit

UPR 3212 - Institut des Neurosciences Cellulaires et Intégratives (INCI)
5, rue Blaise Pascal, 67084 STRASBOURG

Group

Name: Lumière, rythmes circadiens, homéostasie du sommeil et neuropsychiatrie

Group leader: BOURGIN Patrice - pbourgin@unistra.fr

Group leader's phone: 33388116430

Group organization:
- Chercheurs: 8
- ITA: 2
- Doctorants: 1
- Post-Docs: 1
- Autres: 2

Publications of the team linked to the topic (3 last years):
1) 1.       Tsai JW, Hannibal J, Hagiwara G, Colas D, Ruppert E, Ruby NF, Heller HC, Franken P, Bourgin P. Melanopsin as a sleep modulator: circadian gating of the direct effets of light on sleep and altered sleep homeostasis in Opn4 (-/-) mice. PloS Biology, 2009, 7(6):e1000125. Epub 2009 Jun 9.

2) Hubbard J, Ruppert E, Calvel L, Robin-Choteau L, Gropp CM, Allemann C, Reibel S, Sage-Ciocca D, Bourgin P.
Arvicanthis ansorgei, a Novel Model for the Study of Sleep and Waking in Diurnal Rodents.
Sleep. 2015. Jun 1;38(6):979-88. doi: 10.5665/sleep.4754

3) Non-circadian direct effects of light on sleep and alertness: lessons from transgenic mouse models.
Hubbard J, Ruppert E, Gropp CM, Bourgin P.
Sleep Med Rev. 2013 Dec;17(6):445-52.

About PhD

PhD Director: BOURGIN Patrice - pbourgin@unistra.fr

Phone: 0388116430

Junior advisor: non

Co-tutely: non

Co-Director: non

About PhD topic :

Title: Sleep homeostasis is in the eyes !

Project: Scientific background : Sleep deprivation is a major public health issue because, disrupting sleep homeostasis, it affects physiology and behavior including alertness, performance, metabolism or mood. It is today established that chronic sleep deprivation is a risk factor for cardiovascular, metabolic and neuropsychiatric disorders (depression ...). Indeed, sleep is regulated by a homeostatic process, the amount of lost sleep to be recovered. The biological mechanisms and neural pathways involved remain poorly understood. The main current theory associates to sleep homeostasis a metabolic restorative function performed at the cellular level and mediated by adenosine (during waking metabolic activation, transient energy deficit, elevated adenosine levels favoring the occurrence of deep sleep with, in return, glycogen synthesis and equilibrium of energy balance). Some studies have suggested that disruption of sleep homeostasis in winter is causal to the pathogenesis of seasonal affective disorder, but it has never been shown that light influences the sleep homeostat. Non-visual light effects are primarily mediated by melanopsin (OPN4), a photopigment critical for detecting and conveying light information to the brain.
Our team recently reported that mice lacking melanopsin display a major alteration of sleep homeostasis, an observation that has had a significant impact within our scientific community, since it provides for the first time a biological substrate to link light and sleep homeostasis, prompting us to revisit this issue with appropriate animal models. The objective of this project is to demonstrate that light affects sleep homeostasis, via melanopsin and adenosine, at the retinal level.

objectives:
• Demonstrate that light influences the homeostatic response by conducting sleep deprivation experiments in mice exposed to different light exposure paradigms (especially without phase shifting of circadian rhythms).
• Identify the subtype of melanopsinergic cells involved (using a mouse model with invalidation of Brn3b, a gene expressed only in melanopsin-containing cells projecting on brain structures outside the clock).
• Demonstrate that the sleep homeostatic process affects melanopsin-based phototransduction, quantifying the expression of melanopsin and recording melanopsin cells after sleep deprivation. (This assumes that, if melanopsin influences the sleep homeostat, the homeostatic process should in turn influence the melanopsinergic system).
• Demonstrate that this relationship OPN4 - Sleep Homeostasis involves adenosine and its A1 receptor (using a specific transgenic mouse model i.e. conditional A1 receptor crossed with a cre recombinase model specific of melanopsinergic cells).

Methods:
A standard set of electrodes will be implanted to record sleep and the EEG. Sleep deprivation experiments of various duration (dose response – quantification of sleep homeostat) will be performed in mice exposed to various light exposure regimen. The EEG delta activity (most reliable marker of the homeostatic response) will be quantified by spectrum analysis. Finally, the effects of sleep deprivation on the expression of melanopsin will be studied by qPCR and WB and by electrophysiology in collaboration with Oxford (R Foster, S Peirson). The different techniques required for the study are routinely used in the laboratory and animal models are available, ensuring the feasibility of the project.

Conclusion: This project represents an important and innovative step forward to the understanding of the homeostatic regulation of sleep and opens up important perspectives for understanding the effects of sleep deprivation on physiology and behavior.

Wished skills: The student must have a strong background in neuroscience and a special motivation for studying sleep and chronobiology. He (she) must have an interest in cross-disciplinary projects and should be able to work with team partners.

Expertises which will be acquired during the training: The student will reinforce his/her competences in Neuroscience especially in the sleep and chronobiology field as well as in the field of light and photodetection. The thesis project will allow the student acquiring a large set of techniques. Finally, he (she) will benefit from an scientifically rich environment that will increase his potential as a researcher and his communication skills.