Desensitization of Circadian Responses to Light

描述(由申请人提供)：光是影响人类昼夜节律起搏器的最强大的刺激，因此是研究昼夜节律计时系统基本特性的首选刺激。广泛的研究已经证明，连续光暴露的时间、持续时间、波长、模式和数量会影响光刺激人体昼夜节律、神经内分泌和电生理反应的效果。令人惊讶的是，尽管在低等哺乳动物中有证据表明，这些对光的反应会因先前暴露在白光下而变得不敏感，并可能通过对红光的预适应而增强，但光历史对人类昼夜节律系统的敏感性的影响几乎没有受到关注。在初步研究中，我们发现预先暴露在中等强度的冷白色荧光灯(4100K，200Lux；uW/cm2)中显著减弱了对相同光线暴露的褪黑素抑制，而相同个体在预先暴露于暗光(0.5lux；0.16uW/cm2)后的反应显著减弱。这项拟议的研究旨在检验以下假设：1)单一12小时中强光照射(200勒克斯；uw/cm~2)对褪黑素的抑制将随着先前室内光照强度(200勒克斯；uw/cm~2)的持续时间从1.75小时增加到14小时而更强烈地脱敏；2)光暴露对主观警觉性、EOG和EEC衍生的疲劳测量和认知表现的急性影响将随着先前光照暴露在室内光线下的持续时间从1.75小时增加到14小时而更加强烈地减弱；3)先照射3.5h白光(200lux，uw/cm2)，再照射3.5h红光(620 nm；1.78x10e14光子/cm2/S；57uw/cm2)，褪黑素的抑制和光唤醒作用更强，而连续暴露在同等光子密度的白光下7h(200lux；1.78x10e14光子/cm2/cm2/S；uw/cm2)。我们建议在一项平行的、受试者内的暗光历史对照设计中检验这些假设，以比较先前中强光的不同持续时间(1.75h、3.5h、7h和14h)对褪黑素分泌和警觉性的影响，并与随后3天非常暗淡的背景光强度进行比较。这个项目的结果将进一步加深我们对光刺激在调节昼夜节律中的功效的光学史相关变化的基本理解。此外，该项目将量化先前光照病史的时间尺度，这将能够影响光照疗法在治疗昼夜节律紊乱和SAD方面的效率，以及将光照用作需要长期保持警惕的安全敏感行业(例如，内科/外科住院医生、护士、飞行员、卡车和火车司机、核电站操作员)或许多原发睡眠障碍患者通常经历的日间过度嗜睡的直接、非药理疲劳对策的有效性。

DESCRIPTION (provided by applicant): Light is the most powerful stimulus for influencing the human circadian pacemaker and is therefore the preferential stimulus for investigation of the fundamental properties of the circadian timing system. Extensive research has already demonstrated that the timing, duration, wavelength, pattern and number of consecutive light exposures influence the efficacy of light to stimulate circadian, neuroendocrine and electrophysiological responses in humans. Surprisingly, despite evidence in lower mammals that these responses to light are desensitized by prior exposure to white light and may be enhanced by pre-adaptation to red light, the influence of photic history on the sensitivity of the human circadian timing system has received little attention. In preliminary studies, we showed that prior exposure to a moderate intensity cool white fluorescent light (4100K, 200 lux; 64 uW/cm2) significantly attenuated melatonin suppression to the same light exposure, as compared to the response in the same individuals following pre-exposure to dim light (0.5 lux; 0.16 uW/cm2). The proposed investigation is designed to test the hypotheses that 1) melatonin suppression by a single 12-h moderately bright light exposure (200 lux; 64 uW/cm2) will be more strongly desensitized as the duration of prior light exposure to room light intensity (200 lux; 64 uW/cm2) is increased from 1.75 hours to 14 hours; 2) the acute effect of light exposure on subjective alertness, EOG- and EEC-derived measures of fatigue and cognitive performance will be more strongly attenuated as the duration of prior light exposure to room light is increased from 1.75 hours to 14 hours; and 3) melatonin suppression and arousal by light will be greater if preceded by exposure to 3.5 hours of white light (200 lux, 64 uW/cm2) followed by 3.5 hours of red light (620 nm; 1.78 x 10e14 photons/cm2/s; 57 uW/cm2), as compared to 7 hours continuous exposure to an equal photon density of white light (200 lux; 1.78 x 10e14 photons/cm2/s; 64 uW/cm2). We propose to test these hypotheses in a parallel, within-subjects, dim light history-controlled design to compare the effect of different durations of prior light history of moderately bright light (1.75h, 3.5h, 7h, and 14h) on changes in melatonin secretion and alertness, as compared to that following 3-day very dim background light intensities. The results of this project will further our fundamental understanding of photic history-related changes in the efficacy of light stimuli in modulating circadian regulation. Furthermore, this project will quantify the time scale of prior light history that would be able to affect the efficiacy of light therapy in the treatment of circadian rhythm disturbances and SAD, and in the use of light as a direct, non-pharmacological fatigue countermeasure for safety-sensitive industries where prolonged vigilance is required (e.g. medical/surgical residents, nurses, pilots, truck and train drivers, nuclear power plant operators) or for the excessive day-time sleepiness experienced commonly by many patients with primary sleep disorders.