Influence of light history on circadian photobiological responses

描述（由申请人提供）：进入哺乳动物眼睛的光激活独立于经典视觉系统的神经通路，用于调节昼夜节律。该神经通路对光的响应根据环境背景而变化，因此，非图像形成视觉系统代表了神经可塑性的有吸引力的模型系统。光周期的季节性变化提供了一个丰富的例子，说明光的历史可以显着改变光的昼夜节律调节。具体地，与相对较长的夏季相比，之前夹带到短的冬季样光周期导致大约两倍的最大相移（Goldman和Elliott，1988; Evans等人，2004年）。尽管光周期有如此显着的影响，但令人惊讶的是，对这些发现的后续行动却很少。最近的初步工作证实了光周期对昼夜节律反应的影响，并进一步证明了先前被携带到短光周期的动物中相位提前的敏感性增加，进一步完善了我们对光周期如何调节光响应的理解。通过测试各种昼夜输出在一系列的辐照度，我们的目标是确定是否光周期的历史影响阈值，灵敏度，增加率，和/或最大的光响应。我们计划检查行为相移，褪黑激素抑制和各种生化标志物，以最终确定调节水平，通过该调节水平，先前的光史调节昼夜节律输入对光的敏感性。将采用轮跑活动节律评估相位，通过光脉冲前和光脉冲后血浆水平的放射免疫测定法测量夜间褪黑激素抑制，并将使用免疫细胞化学技术鉴定负责迄今为止进行的研究中观察到的敏感性行为差异的分子机制。一旦收集了每项研究的全部数据，将每组的注量-反应曲线拟合到参数模型，确定半饱和常数（即ED 50），ED 50的显著差异将揭示灵敏度的差异。将通过ANOVA分析来自每组的数据，并且将用事后检验评估组间的统计学差异，并且如果p<0.05则确定为显著。这些项目的结果应有助于进一步阐明光的历史调制的昼夜节律调节光的效力的神经机制。 公共卫生相关性：我们的目的是确定环境因素和神经机制，影响光的敏感性，调节昼夜节律。了解光敏感性是如何控制的，将有助于识别潜在的潜在生理异常，以及如何优化光疗法，以治疗情感障碍和昼夜睡眠障碍。

DESCRIPTION (provided by applicant): Light entering the mammalian eye activates a neural pathway independent of the classical visual system, serving to regulate circadian rhythms. This neural pathway's response to light varies according to environmental context and thus, the non-image forming visual system represents an attractive model system of neural plasticity. Seasonal changes in photoperiod provide a rich example of how photic history can markedly change circadian regulation by light. Specifically, prior entrainment to a short winter-like photoperiod results in an approximately two-fold greater maximal phase shift as compared to relatively longer summer days (Goldman and Elliott, 1988; Evans et al., 2004). Despite this significant effect of photoperiod, surprisingly little has been done to follow-up on those findings. Recent preliminary work confirms the photoperiodic influence on circadian responsiveness and further demonstrates an increased sensitivity for phase advances in animals previously entrained to a short photoperiod, further refining our understanding of how photoperiod modulates photic response. By testing a variety of circadian outputs across a range of irradiances, we aim to determine whether photoperiodic history influences threshold, sensitivity, rate of increase, and/or maximal response to light. We plan to examine behavioral phase shifting, melatonin suppression and various biochemical markers in order to ultimately identify the level of regulation by which prior photic history modulates sensitivity to light for circadian input. Wheel-running activity rhythms will be employed to assess phase, nocturnal melatonin suppression will be measured via radioimmunoassay of pre- and post-light pulse plasma levels, and immunocytochemistry techniques will be used to identify the molecular mechanisms responsible for the behavioral differences in sensitivity observed in studies conducted thus far. Once a full complement of data have been collected for each study, fluence-response curves for each group will be fit to a parametric model, the half-saturation constant (i.e. ED50) will be determined, and significant differences in the ED50 will reveal differences in sensitivity. Data from each group will be analyzed via ANOVA, and statistical differences between groups will be assessed with post-hoc tests and determined significant if p<0.05. The results of these projects should serve to further elucidate the neural mechanisms by which photic history modulates the potency of light for circadian regulation. PUBLIC HEALTH RELEVANCE: We aim to determine the environmental factors and neural mechanisms that influence sensitivity to light for regulation of circadian rhythms. Understanding how light sensitivity is controlled will help to identify potential underlying physiological abnormalities as well as ways in which light therapy may be optimized for treatment of affective disorders and circadian sleep disturbances.