Desensitization of Circadian Responses to Light

描述（由申请人提供）：光是影响人体昼夜节律起搏器的最强刺激，因此是研究昼夜节律计时系统基本特性的首选刺激。广泛的研究已经表明，连续光照的时间、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功效。令人惊讶的是，尽管在低等哺乳动物中有证据表明，这些对光的反应通过先前暴露于白色光而脱敏，并且可以通过预先适应红光而增强，但光史对人类昼夜节律计时系统的敏感性的影响很少受到关注。在初步研究中，我们发现，先前暴露于中等强度的冷白色荧光灯（4100 K，200勒克斯; 64 uW/cm 2）显着衰减褪黑激素抑制相同的光暴露，相比，在相同的个人预先暴露于昏暗的光（0.5勒克斯; 0.16 uW/cm 2）。本研究旨在验证以下假设：1）单次12小时中等亮度光照对褪黑激素的抑制作用（200 lux; 64 uW/cm 2）将更强烈地脱敏，因为先前光暴露于室内光强度的持续时间（200 lux; 64 uW/cm 2）从1.75小时增加到14小时; 2）光暴露对主观警觉性的急性影响，当先前暴露于室内光的持续时间从1.75小时增加到14小时时，EOG和EEC衍生的疲劳和认知表现的测量将更强烈地衰减;以及3）如果在光照射之前暴露于3.5小时的白色光，则光引起的褪黑激素抑制和唤醒将更大（200 lux，64 uW/cm 2），然后是3.5小时的红光（620 nm; 1.78 x 10 e14光子/cm 2/s; 57 uW/cm 2），与连续暴露于相同光子密度的白色光7小时相比（200勒克斯; 1.78 x 10 e14光子/cm 2/s; 64 uW/cm 2）。我们建议在一个平行的，受试者内，昏暗的光历史控制的设计来测试这些假设，比较不同的持续时间的先前的光历史的中度明亮的光（1.75小时，3.5小时，7小时，和14小时）的褪黑激素分泌和警觉性的变化的影响，相比，以下3天非常昏暗的背景光强度。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调节中的功效的光历史相关变化的基本理解。此外，该项目将量化先前光史的时间尺度，其能够影响光疗法在昼夜节律紊乱和SAD治疗中的效率，以及在需要长期警惕的安全敏感行业中使用光作为直接的非药理学疲劳对策（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）或许多原发性睡眠障碍患者通常经历的白天过度嗜睡。

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.