The retinal clock in mammals: role in health and disease

Abstract

Abstract:The mammalian retina contains an extraordinary diversity of cell types that are highly organized into precise circuits to perceive and process visual information in a dynamic manner and transmit it to the brain. Above this builds up another level of complex dynamic, orchestrated by a circadian clock located within the retina, which allows retinal physiology, and hence visual function, to adapt to daily changes in light intensity. The mammalian retina is a remarkable model of circadian clock because it harbors photoreception, self-sustained oscillator function, and physiological outputs within the same tissue. However, the location of the retinal clock in mammals has been a matter of long debate. Current data have shown that clock properties are widely distributed among retinal cells and that the retina is composed of a network of circadian clocks located within distinct cellular layers. Nevertheless, the identity of the major pacemaker, if any, still warrants identification. In addition, the retina coordinates rhythmic behavior by providing visual input to the master hypothalamic circadian clock in the suprachiasmatic nuclei (SCN). This light entrainment of the SCN to the light/dark cycle involves a network of retinal photoreceptor cells: rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs). Although it was considered that these photoreceptors synchronized both retinal and SCN clocks, new data challenge this view, suggesting that none of these photoreceptors is involved in photic entrainment of the retinal clock. Because circadian organization is a ubiquitous feature of the retina and controls fundamental processes, the coherence from cell to tissue is critical for circadian functions, and disruption of retinal clock organization or its response to light can potentially have a major impact on retinal pathophysiology and vision.

Rods contribute to the light-induced phase shift of the retinal clock in mammals

“…The retinal clock is composed of a network of multiple strongly coupled circadian oscillators located within distinct cellular layers [ 16 , 30 , 45 , 74 ]. Photoreceptors (cones and ipRGCs) have also been shown to contain a cellular circadian clock (for review, see [ 2 ]), with the notable exception of rods. All of the mouse models examined in the present study ( Opn4 −/− :: Per2 Luc , TRβ −/− :: Per2 Luc , Opn4 −/− :: TRβ −/− :: Per2 Luc , and Opn4 −/− :: rd/rd :: Per2 Luc ) exhibit shortening of the endogenous period, except the Nrl −/− :: Per2 Luc mouse model.…”

“…The mammalian retina contains an endogenous timekeeping system that ensures the fine tuning of its physiology to daily changes in light intensity [ 1 ]. The retinal clock controls the timing of a broad range of essential physiological and metabolic functions (for review, see [ 2 ]), including melatonin release [ 1 , 3 ], dopamine synthesis [ 4 ], photoreceptor disk shedding and phagocytosis [ 5 – 8 ], expression of immediate early genes and visual photopigments [ 9 , 10 ], electrical coupling between photoreceptors [ 11 – 13 ], the electroretinogram b-wave amplitude [ 14 ], circadian clock gene expression [ 15 , 16 ], and visual processing [ 14 , 17 ]. The retina also plays a key role in photic entrainment of the central clock located in the suprachiasmatic nucleus (SCN).…”

Diabetic photoreceptors: Mechanisms underlying changes in structure and function

“…Mechanisms of phototransduction-associated damage in the context of diabetes have not been actively explored. However, recent evidence suggests that light entrainment by rod photoreceptors plays a primary role in setting the mammalian retinal clock (Calligaro et al, 2019), which operates even in the absence of functional vision and controls numerous aspects of retinal physiology such as photoreceptor disk shedding and phagocytosis, and transcription of thousands of retinal genes (Felder-Schmittbuhl et al, 2017). If inflammation is potentiated by synchronization of retinal physiological processes such as peak transcription and peak oxidative stress, then altering the retinal clock by dark rearing (or loss of phototransduction) could eliminate the transcriptional trigger for inflammation, decoupling oxidative stress from inflammation and potentially decelerating the progression of DR.…”

Ocular Clocks: Adapting Mechanisms for Eye Functions and Health

“… 14 This observation triggered extensive analysis of retinal physiology over the 24-hour cycle and many molecular and cellular processes are now known to be under clock-control. 15 , 16 These extend from the expression of photopigments 17 , 18 to visual sensitivity, as reflected in ERG by the amplitude of the photopic b-wave. 19 – 21 They also include processes linked to retina survival such as rhythms in shedding of rod and cone outer segments and phagocytosis by the underlying RPE 22 , 23 and the vulnerability to phototoxicity.…”