The melanopsin-driven pupillary light reflex in seasonal affective disorder

季节性情感障碍中黑视蛋白驱动的瞳孔光反射

• 批准号: 8516114
• 负责人: KATHRYN A ROECKLEIN
• 金额: $ 7.33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516114
• 关键词: Affect; Animals; Antidepressive Agents; Base Sequence; Biological; Biological Markers; Biology; Cells; Chronic; Circadian Rhythms; Code; Control Groups; Data; Depressed mood; Diagnosis; Disease; Disease remission; Economic Burden; Etiology; Family; Frequencies; Genes; Genetic Variation; Genotype; Hibernation; Individual; Individual Differences; Lead; Light; Lighting; Major Depressive Disorder; Mammals; Measurement; Mediating; Mental Depression; Mental Health; Miosis disorder; Mus; Pathway interactions; Patients; Pattern; Phototherapy; Population; Predisposition; Proteins; Pupil; Pupil light reflex; Recording of previous events; Recruitment Activity; Recurrence; Relative (related person); Retinal; Retinal Ganglion Cells; Risk; Risk Marker; Role; Seasonal Affective Disorder; Seasonal Variations; Seasons; Signal Transduction; Testing; Time; Treatment Failure; Treatment Protocols; Variant; Workplace; base; circadian pacemaker; comparison group; cost; day length; depressive symptoms; design; disorder control; falls; melanopsin; response; social; stem; trait; young adult

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.

描述（由申请人提供）：季节性情感障碍（SAD）的特征是季节性模式的复发性抑郁发作，最常发生在秋季和冬季。虽然SAD的机制尚不清楚，但有一种假说认为，季节性日光变化会导致异常。这是由抑郁发作的定期冬季时间，生物学的季节性变化以及光线疗法（LT）对SAD的益处所暗示的。SAD患者对光的反应降低可能是视网膜信号异常的结果，例如冬季的低日光水平低于所需的阈值，导致抑郁症。异常的视网膜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，这些细胞表达蛋白质黑视素并向昼夜节律钟传递有关白天长度的信息。这些细胞还驱动瞳孔光反射的一部分，称为照明后瞳孔响应（PIPR），其中瞳孔在光偏移后收缩。研究发现，与正常小鼠相比，缺失黑视素基因的小鼠PIPR降低。敏感性降低的黑视蛋白途径可以解释SAD的风险。为了支持这一假设，我们最近发现SAD患者在黑视素基因中具有更高频率的特定序列变异。我们现在将测试与健康对照相比，SAD患者的PIPR是否降低，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个体与非季节性、非抑郁对照组以及有非季节性重度抑郁症病史的个体相比，PIPR是否不同。我们将使用黑视蛋白最敏感的特定波长的蓝光。基于动物研究和我们的初步数据，我们预测，与没有抑郁症史的个体相比，SAD患者对蓝光的PIPR会降低，并且与非季节性抑郁症模式的个体相比。(2)确定与对照组相比，SAD患者在PIPR上的季节变化是否不同。(3)确定黑视素基因编码变异的个体是否在PIPR上存在差异。这些测试将使我们能够确定黑视素驱动的PIPR是否基于抑郁症诊断、抑郁发作的季节模式、测量季节或黑视素基因的序列变异而不同。我们的初步数据表明，SAD患者对蓝光的PIPR降低。如果SAD中对日光季节性减少的异常反应源于低黑视蛋白细胞敏感性，则PIPR可能用作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视蛋白介导的，黑视蛋白途径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机制，并可能确定一个临床上有用的SAD风险标志物。

项目成果

Sleep in seasonal affective disorder.

• DOI: 10.1016/j.copsyc.2019.08.023
• 发表时间: 2020-08
• 期刊: Current opinion in psychology
• 影响因子: 5.9
• 作者: Wescott DL;Soehner AM;Roecklein KA
• 通讯作者: Roecklein KA

The role of beliefs about sleep in nightly perceptions of sleep quality across a depression continuum.

• DOI: 10.1016/j.jad.2022.05.092
• 发表时间: 2022-08-15
• 期刊: JOURNAL OF AFFECTIVE DISORDERS
• 影响因子: 6.6
• 作者: Carney, Alison E.;Wescott, Delainey L.;Carmona, Nicole E.;Carney, Colleen E.;Roecklein, Kathryn A.
• 通讯作者: Roecklein, Kathryn A.

Melanopsin, photosensitive ganglion cells, and seasonal affective disorder.

• DOI: 10.1016/j.neubiorev.2012.12.009
• 发表时间: 2013-03
• 期刊: NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
• 影响因子: 8.2
• 作者: Roecklein, Kathryn A.;Wong, Patricia M.;Miller, Megan A.;Donofry, Shannon D.;Kamarck, Marissa L.;Brainard, George C.
• 通讯作者: Brainard, George C.