The melanopsin-driven pupillary light reflex in seasonal affective disorder

描述(由申请人提供)：季节性情感障碍(SAD)的特征是反复发作的具有季节性模式的抑郁发作，最常发生在秋季和冬季。尽管SAD背后的机制尚不清楚，但有一种假说认为，异常是对日光季节变化的反应。这是由于冬季抑郁症发作的规律、生物学的季节性变化以及光疗法(LT)对SAD的好处所表明的。SAD患者对光的反应减弱可能是视网膜信号异常的结果，导致冬季低日光水平降至所需阈值以下，导致抑郁。视网膜的异常反应可能是由于最近发现的一类视网膜神经节细胞的异常，这些细胞表达黑素蛋白，并向生物钟传递关于白天长度的信息。这些细胞还驱动被称为照明后瞳孔反应(PIPR)的部分瞳孔光反射，在这种反应中，瞳孔在光偏移后收缩。研究发现，与正常小鼠相比，缺失黑素基因的小鼠的PIPR降低。敏感性降低的黑素途径可以解释SAD的风险。为了支持这一假说，我们最近发现，SAD患者在黑素蛋白基因的特定序列变异的频率更高。我们现在将测试与健康对照组相比，SAD患者的PIPR是否减少，以及以下其他假设。这项建议的具体目标有三个方面： (1)确定SAD患者的PIPR是否与非季节性、非抑郁对照组以及与有非季节性重度抑郁病史的个体相比有所不同。我们将使用特定波长的蓝光，黑色素对此最敏感。基于动物研究和我们的初步数据，我们预测，与没有抑郁症病史的人相比，SAD患者对蓝光的PIPR将减少，并且相对于有非季节性抑郁模式的人。(2)确定与对照组相比，SAD患者在PIPR上的不同季节是否存在差异。(3)确定黑素基因编码变异的个体在PIPR上是否存在差异。这些测试将使我们能够确定黑色素驱动的PIPR是否根据抑郁诊断、抑郁发作的季节性模式、测量季节或黑素基因的序列变化而有所不同。我们的初步数据表明，SAD患者对蓝光的PIPR减少。如果SAD患者对日光季节性减少的异常反应源于黑素细胞的低敏感性，则PIPR可能作为SAD的生物标志物。其次，在某种程度上，对光的异常反应可能是由黑素介导的，黑素途径中的遗传变异可能会预测PIPR缺陷。如果得到证实，这些观察结果将有助于我们理解抑郁症季节性模式的潜在机制，并可能确定一个临床上有用的SAD风险标记。

DESCRIPTION (provided by applicant): Seasonal affective disorder (SAD) is characterized by recurrent depressive episodes with a seasonal pattern, most often occurring in fall and winter. Although the mechanisms underlying SAD remain unknown, one hypothesis postulates abnormalities in response to seasonal variation in day light. This is suggested by the regular winter timing of depressive episodes, seasonal changes in biology, and the benefit of light therapy (LT) for SAD. A decreased response to light among SAD patients may be the result of abnormal retinal signaling, such that low day light levels in the winter fall below a required threshold, leading to depression. Abnormal retinal responses could be due to abnormalities in a recently discovered class of retinal ganglion cells that express the protein melanopsin and convey information to the circadian clock about day length. These cells also drive a portion of the pupil light reflex termed the post-illumination pupil response (PIPR), in which the pupil constricts after light offset. Studies have found that mice missing the melanopsin gene have a reduced PIPR compared to that seen in normal mice. A melanopsin pathway with reduced sensitivity could explain the risk for SAD. In support of this hypothesis, we recently found that SAD patients have a higher frequency of a particular sequence variation in the melanopsin gene. We will now test if those with SAD have a diminished PIPR compared to healthy controls, as well as the following other hypotheses. The specific objectives of this proposal are three-fold: (1) To determine if individuals with SAD differ in the PIPR relative to nonseasonal, nondepressed controls and in comparison to individuals with a history of nonseasonal Major Depressive Disorder. We will use a specific wavelength of blue light to which melanopsin is most sensitive. Based on animal studies and our preliminary data, we predict that individuals with SAD will have a diminished PIPR to blue light relative to individuals who do not have a history of depression, and relative to individuals with a nonseasonal depression pattern. (2) To determine if individuals with SAD vary across the seasons on the PIPR in comparison to controls. (3) To determine if individuals with coding variations in the gene for melanopsin differ on the PIPR. These tests will allow us to determine if the melanopsin-driven PIPR differs on the basis of depression diagnosis, seasonal pattern of depressive episodes, season of measurement, or sequence variations in the melanopsin gene. Our preliminary data indicate that individuals with SAD have a diminished PIPR to blue light. If the abnormal response to seasonal reductions in day light in SAD stems from low melanopsin cell sensitivity, it is possible that the PIPR may serve as a biomarker for SAD. Secondly, to the extent that abnormal responses to light may be mediated by melanopsin, genetic variation in the melanopsin pathway might be expected to predict PIPR deficits. If confirmed, these observations would contribute to our understanding of the mechanisms underlying a seasonal pattern of depression and possibly identify a clinically useful marker of risk for SAD.