The Circadian Response of Intrinsically Photosensitive Retinal Ganglion Cells

Abstract

Intrinsically photosensitive retinal ganglion cells (ipRGC) signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central) or intrinsic (retinal) network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18–30 years) with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC) and outer retina (cone photoreceptors) was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux). Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO) was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin) retinal ganglion cells mediate this circadian variation.

Image and Non-Image Forming Melanopsin Function in Age-Related Macular Degeneration

“…The data were fitted with linear and exponential models Zele, Feigl, Smith & Markwell 2011) and the pupil light reflex (PLR) defined in terms of baseline pupil diameter (average pupil diameter before light stimulus onset), constriction amplitude (minimum pupil diameter during onset of light stimulus) and post-illumination pupil response (PIPR) (sustained pupil constriction after light stimulus offset). The newly defined PAP (phase amplitude percentage) metric , calculated as ( 638 −464 638 ) 100, used the phasic response during light stimulation to measure inner and outer retinal interactions.…”

“…This provided a retinal irradiance of 14.5 log quanta.cm -2 .s -1 for short wavelength and 14.9 log quanta.cm Figure 5.1 shows the average pupil light reflex of 20 control participants with no retinal abnormalities in response to an 11.9 s, 0.5 Hz sinewave stimulus of long (638 nm; red) or short (464 nm; blue) wavelength light. The PLR was described with linear and exponential models Zele et al 2011) and analyzed according to protocols defined by Adhikari, Zele and Feigl (2015b). To control for individual differences in resting pupil diameter, all data are reported as a percentage of the resting baseline pupil diameter (average pupil diameter during 10 s pre-stimulus period).…”

“…The PSQI has high test-retest reliability (Backhaus, Junghanns, Broocks, Riemann & Hohagen 2002;Buysse et al 1989), as well as a diagnostic sensitivity of 89.6% and specificity of 86.5% (Buysse et al 1989). The PSQI has been used to determine sleep disturbances in glaucoma (Ayaki et al 2016;Wang et al 2013) and the circadian response of ipRGCs (Zele et al 2011).…”

“…A number of metrics have been used to define ipRGC response, namely redilation velocity (Feigl et al 2011b;Zele et al 2011), 6 s PIPR (Park et al 2011), plateau PIPR (Gamlin et al 2007;Markwell et al 2010) and area under curve (AUC) (Herbst et al 2011). In this study, we used the 6 s and plateau PIPR metrics to measure ipRGC controlled PIPR following a recent study by Adhikari et al (2015b) who demonstrated that these metrics show the lowest coefficient of variation for inter and intra-individual measurements.…”

“…Non-image forming functions of these cells include signalling irradiance information for synchronising the circadian body clock to the solar day thus mediating photoentrainment through projections to the suprachiasmatic nucleus (SCN) (Chen, Badea & Hattar 2011;Zele et al 2011) and sleep induction through activation of the ventrolateral preoptic area (Gooley, Lu, Fischer & Saper 2003;Hattar et al 2002). IpRGC dysfunction could therefore alter sleep-wake cycles…”