Photic and Nonphotic Input to the Human Circadian System

描述(申请人提供)：在上一项名为“携带人体昼夜节律起搏器的后效”的资助中，我们能够证明非光时间提示对完全失明的受试者的昼夜节律产生相移效应，这些受试者虽然无法将非24小时的昼夜节律带入社会，但能够比之前认为的更大程度地改变相位。我们还发现，在没有光感知的情况下，完整的昼夜节律光接收(即眼睛暴露在白光下后维持褪黑素抑制反应)的流行率比先前的研究表明的更高。在目前的续期申请中，我们建议进一步调查这些初步调查结果。在筛选以测试是否存在完整的昼夜节律光接收反应之后，受试者将进入两项研究中的一项。 研究1将研究那些对光的昼夜节律反应完整的人，并检查在没有明视和暗视光接收的情况下昼夜节律光接收的光谱敏感性。这些结果将与已经在视力受试者中完成的类似研究进行比较，这些受试者同时保持昼夜和明视/暗视的光接收，以评估这些光感受器系统对昼夜反应的相对贡献。研究2将研究那些不受光线影响的人，并将确定非光时间线索(睡眠-醒来、休息-活动、吃饭、淋浴、社交)的携带限度，以便确定这些时间线索的强度，用于治疗。具体来说，我们将检验以下假设：研究1)在生物夜的早期，暴露于460 nm的单色光6.5h会导致昼夜相延迟3h，松果体褪黑素的产生受到85%的抑制，而同样的555 nm光子密度暴露对昼夜相或褪黑素的抑制没有影响(与视力受试者的1.7h延迟和37%的抑制相比)；研究2)暴露在相对于基线固有周期提前0.4h的非光周期中，将导致0.4h的周期提前。这项工作对于理解人类中存在的光的昼夜节律和非成像效应的新的光感受器系统(S)具有重要意义，并通过定义非光同步器的携带限度来进一步理解非光时间线索对人类昼夜节律起搏器的影响，以便潜在地评价这种时间线索在盲人和视力人群中治疗昼夜节律睡眠-觉醒障碍的有效性

DESCRIPTION (provided by applicant): In the previous grant, 'After-effects of entrainment of the human circadian pacemaker', we were able to demonstrate that non-photic time cues elicited a phase-shifting effect on circadian rhythms in totally blind subjects that, while unable to entrain non-24-hour circadian rhythms in society, was able to modify phase to a greater extent than previously thought. We also discovered that the prevalence of intact circadian photoreception (i.e., maintenance of the melatonin suppression response following ocular exposure to white light) in the absence of light perception was greater than prior studies suggested. In the current renewal application, we propose to further investigate these initial findings. Following screening to test for the presence or absence of an intact circadian photoreception response, subjects will enter one of two studies. Study 1 will study those with an intact circadian response to light and examine the spectral sensitivity of circadian photoreception in the absence of photopic and scotopic photoreception. These results will be compared with similar studies that have already been completed in sighted subjects who maintain both circadian and photopic/scotopic photoreception to assess the relative contributions of these photoreceptor systems to circadian responses. Study 2 will study those who are not affected by light and will determine the limits of entrainment for non-photic time cues (sleep-wake, rest-activity, meals, showers, social contact) in order that the strength of such time cues can be determined for therapeutic use. Specifically we will test the hypotheses that: Study 1) exposure to monochromatic light of 460 nm for 6.5 h in the early biological night will cause a 3 h delay in circadian phase and a 85 percent suppression in pineal melatonin production whereas exposure to the same photon density of 555 nm will have no effect on circadian phase or melatonin suppression (compared to 1.7 h delay and 37 percent suppression in sighted subjects); Study 2) Exposure to a non-photic schedule advanced by 0.4 h relative to baseline intrinsic period will cause a phase advance of period of 0.4 h. This work has significant implications for understanding the novel photoreceptor system(s) underlying circadian and non-image-forming effects of light in humans and for further understanding the impact of non-photic time cues on the human circadian pacemaker by defining the limits of entrainment for non-photic synchronizers in order to potentially evaluate the efficacy of such time cues for treatment of circadian rhythm sleep-wake disorders in both the blind and sighted populations