Impact of sex and age on non-visual light input that affects sleep and circadian rhythms

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Project Summary/Abstract Light is processed in the eye for both visual and non-visual [i.e., non-image-forming (NIF)] pathways. NIF pathway targets include circadian rhythms, hormones (e.g., melatonin, which is important in sleep and circadian rhythms), heart rate, EEG, mood, and pupillary light response physiology. NIF pathway targets are central to many circadian, sleep, psychiatric, and neurologic health outcomes whose risks and progression vary by sex and age. It is therefore important to document whether the response to light input to the NIF pathway and its targets differ by sex and age because of their potential contribution to the pathogenesis, risk, and/or severity of some disorders; this should facilitate targeted diagnosis, monitoring, and treatment strategies. Intrinsically photosensitive retinal ganglion cells containing melanopsin are the primary sensors for NIF processing, whose response to light stimuli’s wavelength, intensity, and duration differ from those of rods and cones. We will test the hypothesis that the responsiveness of the melanopsin pathway depends on sex and age. A method for probing the response of the melanopsin pathway uses the post-illumination pupil response (PIPR) which can be documented using commercially available pupillometers in sessions lasting less than an hour by trained staff with results available almost immediately. PIPR is reported to be altered in individuals with circadian sleep/wake, psychiatric, and neurologic disorders that have different distributions by sex and age. There are four problems with prior studies using PIPR that severely limit interpretation and translation of the prior work: (i) not designed to test for sex and age effects; (ii) considerable variation in stimuli and analysis methods; (iii) stimuli that may not be melanopsin-pathway specific; and (iv) no documentation of time- dependent response variation by sex and age. Sex or age differences would require appropriate study population composition to avoid confounding. The most frequently used test of the melanopsin pathway for NIF-influenced circadian rhythms is light-induced melatonin suppression. This method requires multiple hours of data collection over two nights, is onerous for participants, has expensive assay costs, and does not provide results in close-to-real time. We will test for sex and age differences in PIPR in 48 healthy individuals (1:1 for F:M; and 1:1:1 for age groups 18-40, 40-60 and 60-85 years). Individuals will have (i) pupillometry with specific durations, light wavelengths and intensities chosen to primarily affect the melanopsin pathway (M+) or not (M-) at three different clock times; (ii) melatonin suppression testing using M+ and M- stimuli from portable light boxes; and (iii) documentation of circadian phase and sleep timing. We will calculate multiple measures of PIPR (including pupil size at 6 sec, time-varying changes in pupil size and others); these will be correlated with melatonin suppression, circadian phase, and sleep timing. As a resource for standardization of methods, we will make available our data cleaning and analyses programs on a public website. Increased use of pupillometry could be beneficial for further investigations of NIF pathway-related sex- and age- related differences in health and disease; clinical applications including diagnosis and monitoring before disease symptoms emerge; and design and testing of personalized targeted interventions including retina-based therapies and/or light exposure.