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

项目摘要/摘要 光在眼睛中被处理为视觉和非视觉[即，非成像(NIF)]路径。NIF途径靶点 包括昼夜节律、荷尔蒙(例如，在睡眠和昼夜节律中很重要褪黑素)、心率、EEG 情绪，以及瞳孔光反应生理学。NIF通路靶点是许多昼夜节律、睡眠、精神和 神经学健康结局，其风险和进展因性别和年龄而异。因此，重要的是记录 NIF通路及其靶点对光输入的反应是否因其潜力而因性别和年龄而不同 对某些疾病的发病机制、风险和/或严重性的贡献；这应该有助于有针对性的诊断， 监测和治疗策略。 含有黑素的本质上敏感的视网膜神经节细胞是处理NIF的主要传感器，其 对光刺激的反应波长、强度和持续时间不同于视杆细胞和视锥细胞。我们将测试 黑素途径的反应性取决于性别和年龄的假设。一种探查数据的方法 黑素途径的反应使用光照后的瞳孔反应(PIPR)，这可以用 由训练有素的工作人员在不到一小时的时间内提供商业化的瞳孔测量仪，结果几乎可用 立刻。据报道，在有昼夜睡眠/清醒、精神和神经紊乱的个体中，PIPR会发生改变。 按性别和年龄有不同的分布。之前使用PIPR的研究存在四个问题，严重限制了 对先前工作的解释和笔译：(1)不是为了测试性别和年龄的影响；(2)在 刺激物和分析方法；(Iii)可能不是黑素途径特异性的刺激物；以及(Iv)没有时间记录- 依存性反应随性别和年龄的变化。性别或年龄差异将需要适当的研究人群 构图以避免混淆。NIF影响昼夜节律的最常用的黑素途径测试 节律是光诱导的褪黑素抑制。这种方法需要在两个晚上收集多个小时的数据， 对参与者来说很繁重，检测成本很高，而且不能提供接近实时的结果。 我们将测试48名健康个体的PIPR的性别和年龄差异(女性：男性为1：1；18-40岁年龄组为1：1：1， 40-60岁和60-85岁)。个人将进行(I)具有特定持续时间、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素途径(M)或不影响(M-)；(Ii)褪黑激素抑制 使用便携式灯箱中的M和M刺激进行测试；以及(Iii)记录昼夜节律和睡眠时间。我们 将计算PIPR的多个测量(包括6秒时的瞳孔大小、随时间变化的瞳孔大小和其他)；这些 将与褪黑激素抑制、昼夜节律和睡眠时间相关。 作为方法标准化的资源，我们将公开我们的数据清理和分析程序 网站。增加对斜视测量的使用可能有助于进一步研究与性别和年龄相关的NIF通路。 健康与疾病的相关区别；临床应用，包括疾病症状前的诊断和监测 出现；以及个性化目标干预的设计和测试，包括基于视网膜的治疗和/或光照。

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.