CV Science

Ouria Dkhissi-Benyahya PhD Neurosciences

Course and current status

EDUCATION

2010  HDR: Mechanisms of Circadian Photoreception     University Claude Bernard, Lyon 1

1996  PhD in Neurosciences                               University of Pierre et Marie Curie, Paris 6

1992  DEA (M2) in Sensory Neurobiology                                    University of Montpellier

1986  Baccalaureate in Experimental Sciences                   Université des Sciences, Oujda (Maroc)    

PROFESSIONAL POSITIONS  

2021-   Co-head, team « Chronobiology and Affective Disorders »  INSERM U1208, Bron

2005-   Senior Research Scientist (CR1), Department of Chronobiology, INSERM U846, Bron

2001    Research Scientist (CR2), Team INSERM U371, Bron

97-01   Post-doc, INSERM U371, Bron

1996    Post-doc, UMR6558 , Poitiers

I joined the team "Retina, photoreceptor and circadian regulation” in 1997 (INSERM U371, Bron). My motivations to join this group were first linked to the demonstration during my PhD that the development of a glaucoma-like disorder in an animal model potentially alters daily rhythms of dopamine and melatonin (Dkhissi et al., 1993, 1993, 1996, 1998, 1999, 2001). This result prompted me to broaden my knowledge in circadian rhythms and to focus my research on the master clock of the suprachiasmatic nucleus (SCN). Secondly, it was the only team at that time to assemble a set of methodological and conceptual skills in the field of photobiology, visual system and circadian rhythms.  I was recruited as Chargé de Recherche (CR2) by INSERM in october 2001 and promoted CR1 in october 2006. Since my recruitment, my scientific projects were focalised on circadian photoreception and the photic entrainment of the central and retinal clocks.  I have made major contributions to the field of circadian photoreception and in particular on the mechanisms of photon integration in the suprachiasmatic nucleus (SCN) by first developing a method of quantification of early genes (c-fos) expression in the site of the endogenous clock, the SCN (Rieux et al., J Biol Rhythms 2002). I have shown by this cellular approach that the temporal integration of photons extends on a scale of extremely long time (few seconds to 1 hour) and that the site of integration is at the level of the SCN (Dkhissi-Benyahya et al., J Neurosci 2000). This cellular approach has allowed me to demonstrate a reduction of the effect of light on the photic induction of c-fos, together with an effect on the secretion of melatonin, during normal and accelerated aging in a primate (Aujard et al., Neurosci 2001). In parallel, I developed international collaborations that highlighted 1) the presence of SW cones in a prosimian primate, previously considered as absent in this group (Dkhissi-Benyahya et al., J comp Neurol 2001) 2) cell markers common to photoreceptors in major groups of primates, including humans (Chiquet et al., 2002; Chiquet et al., Brain Res Bull 2005), (3) a new type of "dichromate" cone in rodents (Coexpression of two opsins in the same cone (Lukats et al., 2002) and (4) the demonstration of a new type of melanopsin cone in humans (Dkhissi-Benyahya et al., IOVS, 2006). In 2008, we proposed that the classical view of glaucoma as pathology unique to the visual system should be extended to include anatomical and functional alterations of the circadian timing system (Drouyer et al., 2008). I then established the concept of response domains of different photoreceptors in circadian photoreception and modelled the relative contributions of different types of photoreceptors (Dkhissi-Benyahya et al., Neuron, 2007; Dollet et al., Chronobiol Int 2010).In 2006, We demonstrated an additional regulatory feedback loop involving the clock gene Bmal1 and the Peroxisome Proliferator Activated Receptor-a (PPARa) in peripheral clocks (Canaple et al., Mol Endocrinol 2006) and participate to the development of new mouse model that allow in vivo imaging of peripheral clocks (Canaple et al. Cell Mol Life Sci. 2018). The consequences of pathologies on the functioning and light response of the retinal clock (Lahouaoui et al., PlosOne 2014, Mol Vision 2016) and the circadian system (Fifel et al., Chronobiol Int 2013; PlosOne 2014; Sabbar et al., Front Behav Neurosci 2017) have been also evaluated. Since 2016, we developed in the “Chronobiology and Affective Disorders” team, a new transverse project that aims to identify the neurobiological mechanisms and efficacy of light in depression. We showed the involvement of the glial system in the antidepressant action of deep brain stimulation (Etievant et al, eBioMedicine, 2015; Front Cell Neurosci, 2015) and that the novel multi-model antidepressant vortioxetine, targeting 5-HT7 receptor, affects the phase and the period of clock gene expression in the central clock (Westrich et al. Neuropharmacology, 2015) and presents promnesic effect. Recently, we provide an exhaustive study of rhythmic gene regulation in the non-human primate (Mure et al., Science 2018). I showed that the retinal clock is composed of a network of clocks in which melanopsin play an important role in retinal clock mechanisms (Dkhissi-Benyahya et al., Cell Mol Life Sci, 2013) and highlighted an indispensable role of rods in the phase shift of the retinal clock (Calligaro et al., Plos Biol 2019). Lately, we developed a standardized method to assess the endogenous activity and the light response of the retinal clock (Calligaro et al., Mol Vis 2020). I have a broad background in molecular, cellular, anatomical and behavioral approaches and light manipulations in rodent models. Since 2021, I co-lead the team « Chronobiology and Affective Disorders »,at INSERM U1208.

I participated in over 60 conferences, 23 as invited speaker and in the organisation of  international and national conferences. I was PI (ANR, Retina-France, Institut de France, CMIRA, Pack Ambition International, Cepheldia, FRM) and co-PI (Biomed2, FP5-6, ANR Neuro, ANR-Tecsan, ACI, ACT, USIAS, FRM) of national, european and international grants.

I have been member of the National Commission for University (69-Neurosciences ; 2011-2015), administrative board of the “Société Francophone de Chronobiologie” (SFC), elected general secretary of SFC (2010-2015), board member of the Doctoral School Neurosciences and Cognition of Lyon (since 2010), editorial board member of “Journal of Circadian Rhythms”. I am involved in teaching at master level in Lyon, Paris and in training master and PhD students from Morroco (EuroMediterranean Master of Neurosciences and Biotechnology, Marrakech).

Scientific summary

Circadian 24h rhythms are a fundamental hallmark of every cellular and physiological process throughout the body and are programmed by molecular clocks widely distributed in mammalian tissues and synchronized by a master hypothalamic clock, the suprachiasmatic nucleus (SCN). Circadian clocks generate accurate timing through complex transcriptional/post-translational feedback loops involving transcription factors encoded by clock genes. These complex regulations lead to the rhythmic expression of these genes, with a period close to 24h, thus constituting a timecode for the entire cell. Clock genes activate the expression of “clock controlled genes” at specific times of the cycle, regulating in turn the rhythmic expression of other classes of genes controlling rhythmic cellular functions ranging from cell cycle duration, gene expression, hormonal secretion, cognitive performance to sleep/wake cycle.

In mammals, the strongest synchronizing input to the circadian system is environmental light, which is received by retinal photoreceptor cells (rods, cones and melanopsin-expressing ganglion cells or ipRGCs), and maintains the master clock entrained to the environmental 24h light/dark cycle. Light is also known to modulate brain structures involved in sleep regulation, mood and cognition, via ipRGCs. Aberrant light cycles and/or disrupted circadian rhythmicity are known to produce depressive states and impair cognition. Inversely, light therapy has been proven to be effective in several forms of depression. However, the underlying mechanisms through which light affects brain structures are unknown.

In addition to synchronizing the central clock, the mammalian retina also contains an intrinsic circadian oscillator that plays a crucial function in adapting retina physiology to the light/dark alternation by regulating rod outer segment disc shedding and phagocytosis by the retinal pigment epithelium, expression of immediate early genes and opsin genes in photoreceptors, and dopamine/melatonin synthesis. Moreover, the retinal clock regulates processes that are directly linked to retinal survival such as nocturnal release of the cytoprotective melatonin, photoreceptor outer segment phagocytosis, and phototoxicity. Although these events are critical for retinal functions, it remains unclear how the mammalian retinal circadian clock controls ocular and central physiological rhythmicity and what are the specific roles of the different photoreceptors in light entrainment of local retinal clocks.

By coupling complementary approaches ex vivo, in vivo and in vitro in several critical mouse models, our main projects aim to :

1) Explore how light entrain retinal clocks and determine the molecular mechanisms and the photoreceptors involved in this response during development and in the adult.  

2)  Dissect the neurobiological mechanisms of light in depression. The possible beneficial or deleterious effects of light and the role of melanopsin in mediating this effect will be assess.