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大的刺激，因此是昼夜节律计时系统基本特性研究的首选刺激。广泛的研究已经证明，连续光照的时间、持续时间、波长、模式和次数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，这些对光的反应通过事先暴露于白光而脱敏，并可能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敏感性的影响却很少受到关注。在初步研究中，我们发现，与预先暴露于昏暗光线（0.5勒克斯；0.16 uW/cm2）后的反应相比，事先暴露于中等强度的冷白色荧光灯（4100K， 200勒克斯；64 uW/cm2）可显著减弱褪黑激素对相同光线下的抑制。该研究旨在验证以下假设：1)当先前暴露于室内光强度（200勒克斯，64 uW/cm2）的时间从1.75小时增加到14小时时，单次12小时中等强光照射（200勒克斯，64 uW/cm2）对褪黑激素的抑制作用将更加强烈；2)光照对主观警觉性、EOG和eec衍生的疲劳和认知表现的急性影响将随着先前光照在室内光线下的持续时间从1.75小时增加到14小时而减弱；3)与连续暴露于等光子密度的白光（200勒克斯，64 uW/cm2） 7小时相比，暴露于3.5小时的白光（200勒克斯，1.78 x 10e14光子/cm2/s， 57 uW/cm2）之后，光对褪黑激素的抑制和唤醒作用会更大。我们建议在平行的、受试者内部的、弱光历史控制的设计中检验这些假设，以比较不同持续时间的中度强光（1.75小时、3.5小时、7小时和14小时）对褪黑激素分泌和警觉性变化的影响，与3天非常微弱的背景光强度相比。该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作用的光史相关变化的基本理解。此外，该项目将量化先前光照史的时间尺度，这将能够影响光疗在治疗昼夜节律紊乱和SAD方面的效率，并将光作为需要长期保持警惕的安全敏感行业（例如医疗/外科住院医生、护士、飞行员、卡车和火车司机）的直接、非药物疲劳对策。核电站操作员)或许多原发性睡眠障碍患者普遍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.