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

性别和年龄对影响睡眠和昼夜节律的非视觉光输入的影响

• 批准号: 10733290
• 负责人: Elizabeth B. Klerman
• 金额: $ 53.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733290
• 关键词: Address; Adult; Affect; Age; Area; Biological Assay; Biological Process; Biology; Brain; Cells; Circadian Rhythms; Darkness; Data Analyses; Data Collection; Diagnosis; Diagnostic; Disease; Disease Outcome; Documentation; Electroencephalography; Equipment; Exposure to; Eye; Fostering; Future; Grouping; Health; Heart Rate; Hormones; Hour; Image; Individual; Inpatients; Intervention; Investigation; Light; Lighting; Longevity; Measures; Melatonin; Mental disorders; Methods; Monitor; Moods; National Heart, Lung, and Blood Institute; Neurologic; Outcome; Outcome Measure; Participant; Pathogenesis; Pathway interactions; Persons; Phase; Physiology; Process; Publications; Pupil; Randomized; Reporting; Research; Resources; Retina; Retinal Ganglion Cells; Risk; Sampling; Severities; Sex Differences; Sex Distribution; Shipping; Sleep; Standardization; Stimulus; Strategic vision; Symptoms; Testing; Time; Training; Translations; Variant; Vertebrate Photoreceptors; Vision; Visual; Woman; Work; age difference; age effect; age group; age related; alertness; circadian; clinical application; clinical diagnostics; cognitive function; cost; data cleaning; design; disorder risk; health difference; light effects; melanopsin; men; nervous system disorder; personalized medicine; portability; programs; receptor; resilience; response; saliva sample; sensor; sex; study population; tool; treatment strategy; web site

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.

项目概要/摘要 光在眼睛中针对视觉和非视觉[即非成像（NIF）]途径目标进行处理。 包括昼夜节律、激素（例如，褪黑激素，对睡眠和昼夜节律很重要）、心率、脑电图、 情绪和瞳孔光反应生理学目标是许多昼夜节律、睡眠、精神和疾病的核心。 因此，记录神经系统健康结果的风险和进展因性别和年龄而异。 NIF 通路及其靶标对光输入的反应是否因其潜力而因性别和年龄而异 对某些疾病的发病机制、风险和/或严重程度的贡献；这应有助于有针对性的诊断， 监测和治疗策略。 含有黑视蛋白的本质光敏视网膜神经节细胞是 NIF 处理的主要传感器，其 对光刺激的波长、强度和持续时间的反应与视杆细胞和视锥细胞的反应不同。 假设黑视蛋白通路的反应性取决于性别和年龄。 黑视蛋白通路的反应使用照明后瞳孔反应（PIPR），可以使用以下方法记录 市售瞳孔计，由训练有素的工作人员进行持续不到一小时的会议，几乎可以获得结果 据报道，患有昼夜节律睡眠/觉醒、精神和神经系统疾病的个体的 PIPR 会立即发生改变。 先前使用 PIPR 进行的研究存在四个问题，严重限制了其在性别和年龄上的分布。 先前工作的解释和翻译：(i) 并非旨在测试性别和年龄的影响；(ii) 存在很大差异； 刺激和分析方法；(iii) 可能不是黑视蛋白途径特异性的刺激；以及 (iv) 没有时间记录； 性别和年龄的依赖性反应变化需要适当的研究人群。 成分以避免混淆，是 NIF 影响的昼夜节律黑视蛋白通路最常用的测试。 节律是光诱导的褪黑激素抑制，该方法需要两个晚上的多个小时的数据收集。 对于参与者来说是繁重的，具有昂贵的检测成本，并且不能提供接近实时的结果。 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视蛋白通路（M+）或不影响（M-）（ii）褪黑激素抑制； 使用便携式灯箱的 M+ 和 M- 刺激进行测试；以及 (iii) 记录昼夜节律阶段和睡眠时间。 将计算 PIPR 的多个测量值（包括 6 秒时的瞳孔大小、瞳孔大小随时间的变化等）； 与褪黑激素抑制、昼夜节律阶段和睡眠时间相关。 作为方法标准化的资源，我们将在公共平台上提供我们的数据清理和分析程序 增加瞳孔测量的使用可能有利于进一步研究与性别和年龄相关的 NIF 通路。 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 出现；以及设计和测试个性化的有针对性的干预措施，包括基于视网膜的治疗和/或光照。