Attenuated pupillary light responses and downregulation of opsin expression parallel decline in circadian disruption in two different mouse models of Huntington’s disease

Ouk, Koliane; Hughes, Steven; Pothecary, Carina A.; Peirson, Stuart N.; Morton, A. Jennifer

doi:10.1093/hmg/ddw359

Cited by 19 publications

(22 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For double-labeling experiments, both primary and secondary antibodies were incubated simultaneously. Because both CRY1 and melanopsin antibodies are raised in rabbit, colocalization of CRY1 within ipRGCs was performed using anti-CRY1 and anti–green fluorescent protein antibodies on retinal sections from OPN4.Cre.eYFP mice obtained from previous studies (25). …”

Section: Methodsmentioning

confidence: 99%

Differential roles for cryptochromes in the mammalian retinal clock

et al. 2018

Self Cite

View full text Add to dashboard Cite

Cryptochromes 1 and 2 (CRY1/2) are key components of the negative limb of the mammalian circadian clock. Like many peripheral tissues, Cry1 and -2 are expressed in the retina, where they are thought to play a role in regulating rhythmic physiology. However, studies differ in consensus as to their localization and function, and CRY1 immunostaining has not been convincingly demonstrated in the retina. Here we describe the expression and function of CRY1 and -2 in the mouse retina in both sexes. Unexpectedly, we show that CRY1 is expressed throughout all retinal layers, whereas CRY2 is restricted to the photoreceptor layer. Retinal period 2::luciferase recordings from CRY1-deficient mice show reduced clock robustness and stability, while those from CRY2-deficient mice show normal, albeit long-period, rhythms. In functional studies, we then investigated well-defined rhythms in retinal physiology. Rhythms in the photopic electroretinogram, contrast sensitivity, and pupillary light response were all severely attenuated or abolished in CRY1-deficient mice. In contrast, these physiological rhythms are largely unaffected in mice lacking CRY2, and only photopic electroretinogram rhythms are affected. Together, our data suggest that CRY1 is an essential component of the mammalian retinal clock, whereas CRY2 has a more limited role.—Wong, J. C. Y., Smyllie, N. J., Banks, G. T., Pothecary, C. A., Barnard, A. R., Maywood, E. S., Jagannath, A., Hughes, S., van der Horst, G. T. J., MacLaren, R. E., Hankins, M. W., Hastings, M. H., Nolan, P. M., Foster, R. G., Peirson, S. N. Differential roles for cryptochromes in the mammalian retinal clock.

show abstract

Section: Methodsmentioning

confidence: 99%

Differential roles for cryptochromes in the mammalian retinal clock

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…The SCN synchronizes to the LD of the environment through the action of light received by the light-sensitive retinal ganglion cells (Panda et al, 2002;Ruby et al, 2002). Both R6/2 and Q175 mice-a HD model with slower phenotype development-exhibit progressive retinal morphologic changes, including a downregulation in the expression of melanopsin and cone opsin, markers of retinal light-sensitive and cone cells, respectively (Ouk et al, 2016b;Lin et al, 2019). Photodetection appeared to be progressively impaired in R6/2 mice because they exhibited attenuation in their PLR from 12 weeks of age for light at low intensity.…”

Section: Discussionmentioning

confidence: 99%

“…The first component of the circadian system to be disrupted in HD may be the retinal dysfunction and degeneration that has been described in R6/2 and other HD mice models (Helmlinger et al, 2002;Petrasch-Parwez et al, 2004;Batcha et al, 2012;Ragauskas et al, 2014). A recent study has found deficits in retina function of the R6/2 mouse that might cause disruption of light transmission to the SCN (Ouk et al, 2016b). That study reported a decrease in pupillary light responses (PLRs; or the ability of the pupil to constrict in response to light, a marker of light reception in the retina) that is correlated with down-regulation of the photopigments melanopsin and cone opsin in both R6/2 mice and a full-length knock-in mouse model of HD (Ouk et al, 2016b).…”

Section: Introductionmentioning

confidence: 99%

“…A recent study has found deficits in retina function of the R6/2 mouse that might cause disruption of light transmission to the SCN (Ouk et al, 2016b). That study reported a decrease in pupillary light responses (PLRs; or the ability of the pupil to constrict in response to light, a marker of light reception in the retina) that is correlated with down-regulation of the photopigments melanopsin and cone opsin in both R6/2 mice and a full-length knock-in mouse model of HD (Ouk et al, 2016b). Behaviorally, however, the situation is complex.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Abnormal Photic Entrainment to Phase-Delaying Stimuli in the R6/2 Mouse Model of Huntington's Disease, despite Retinal Responsiveness to Light

Ouk

Aungier

Ware

et al. 2019

eNeuro

Self Cite

View full text Add to dashboard Cite

The circadian clock located in the suprachiasmatic nucleus (SCN) in mammals entrains to ambient light via the retinal photoreceptors. This allows behavioral rhythms to change in synchrony with seasonal and daily changes in light period. Circadian rhythmicity is progressively disrupted in Huntington's disease (HD) and in HD mouse models such as the transgenic R6/2 line. Although retinal afferent inputs to the SCN are disrupted in R6/2 mice at late stages, they can respond to changes in light/dark cycles, as seen in jet lag and 23 h/d paradigms. To investigate photic entrainment and SCN function in R6/2 mice at different stages of disease, we first assessed the effect on locomotor activity of exposure to a 15 min light pulse given at different times of the day. We then placed the mice under five non-standard light conditions. These were light cycle regimes (T-cycles) of T21 (10.5 h light/dark), T22 (11 h light/dark), T26 (13 h light/dark), constant light, or constant dark. We found a progressive impairment in photic synchronization in R6/2 mice when the stimuli required the SCN to lengthen rhythms (phase-delaying light pulse, T26, or constant light), but normal synchronization to stimuli that required the SCN to shorten rhythms (phase-advancing light pulse and T22). Despite the behavioral abnormalities, we found that Per1 and c-fos gene expression remained photo-inducible in SCN of R6/2 mice. Both the endogenous drift of the R6/2 mouse SCN to shorter periods and its inability to adapt to phase-delaying changes will contribute to the HD circadian dysfunction.

show abstract

“…121 Degeneration of cone and melanopsin pathways has also been reported in a mouse model of Huntington's disease. 122 All these data suggest alteration of both retinal photoreception and photic signal transmission necessary to entrain the retinal and the central clocks in several degenerative diseases. Using impaired circadian photoreception as a marker or biological indicator of retinal or brain pathologies will represent a valuable research tool for diagnostic purposes.…”

mentioning

confidence: 99%

The retinal clock in mammals: role in health and disease

Felder-Schmittbuhl¹,

Calligaro²,

Dkhissi-Benyahya³

2017

CPT

View full text Add to dashboard Cite

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.

show abstract

Attenuated pupillary light responses and downregulation of opsin expression parallel decline in circadian disruption in two different mouse models of Huntington’s disease

Cited by 19 publications

References 67 publications

Differential roles for cryptochromes in the mammalian retinal clock

Differential roles for cryptochromes in the mammalian retinal clock

Abnormal Photic Entrainment to Phase-Delaying Stimuli in the R6/2 Mouse Model of Huntington's Disease, despite Retinal Responsiveness to Light

The retinal clock in mammals: role in health and disease

Contact Info

Product

Resources

About