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

项目概要/摘要 光在眼睛中被处理用于视觉和非视觉两者[即，非成像（NIF）途径。NIF通路靶点 包括昼夜节律，激素（例如，褪黑激素，其在睡眠和昼夜节律中是重要的），心率，EEG， 情绪和瞳孔光反应生理学。NIF通路靶点是许多昼夜节律、睡眠、精神病学和免疫学的核心。 神经健康结果，其风险和进展因性别和年龄而异。因此，必须记录 对NIF通路及其靶点的光输入的反应是否因性别和年龄而异，因为它们的潜力 有助于某些疾病的发病机制、风险和/或严重程度;这应有助于靶向诊断， 监测和治疗策略。 含有黑视蛋白的视网膜内光敏神经节细胞是NIF加工的主要传感器，其 对光刺激的波长、强度和持续时间的反应不同于视杆细胞和视锥细胞。我们将测试 黑视素途径的反应性取决于性别和年龄的假设。一种用于探测 黑视蛋白途径的光响应使用照射后瞳孔响应（PIPR），其可以使用 市售瞳孔计，由受过培训的工作人员进行，持续时间不到一小时， 立即据报道，PPR在昼夜睡眠/觉醒、精神病和神经系统疾病的个体中发生改变 在性别和年龄上有不同的分布。使用PIPR的先前研究存在四个问题， 解释和翻译以前的工作：（一）不旨在测试性别和年龄的影响;（二）相当大的变化， 刺激和分析方法;（iii）刺激可能不是黑视蛋白通路特异性的;以及（iv）没有时间记录- 不同性别和年龄的依赖性反应差异。性别或年龄差异需要适当的研究人群 避免混淆。NIF影响的昼夜节律的黑视素途径的最常用测试 是光诱导的褪黑激素抑制。这种方法需要在两个晚上收集多个小时的数据， 对于参与者来说是繁重的，具有昂贵的分析成本，并且不能在接近真实的时间内提供结果。 我们将在48名健康个体中测试PIPR的性别和年龄差异（F：M为1：1; 18-40岁年龄组为1：1：1， 40-60岁和60-85岁）。个人将接受（i）特定持续时间、光波长和强度的瞳孔测量 选择在三个不同的时钟时间主要影响黑视素途径（M+）或不影响（M-）;（ii）褪黑激素抑制 使用来自便携式灯箱的M+和M-刺激进行测试;以及（iii）记录昼夜节律相位和睡眠定时。我们 将计算PIPR的多个测量值（包括6秒时的瞳孔大小、瞳孔大小的时变变化等）;这些 将与褪黑激素抑制、昼夜节律相位和睡眠时间相关。 作为方法标准化的资源，我们将在公共网站上提供我们的数据清理和分析程序。 网站增加瞳孔测量的使用可能有利于进一步研究NIF通路相关的性别和年龄， 健康和疾病的相关差异;临床应用，包括疾病症状前的诊断和监测 以及设计和测试个性化的靶向干预措施，包括基于视网膜的治疗和/或光暴露。

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.