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: 8384930
• 负责人: KATHRYN A ROECKLEIN
• 金额: $ 7.63万
• 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/8384930
• 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. PUBLIC HEALTH RELEVANCE: Major depression is a highly prevalent, chronic, and debilitating mental health problem with significant social cost that poses a tremendous economic burden. Winter seasonal affective disorder (SAD) is a subtype of recurrent major depression involving substantial depressive symptoms that adversely affect the family and workplace for about 5 months of each year during most years, beginning in young adulthood. This proposal aims to study the role of the melanopsin pathway in SAD, in the hopes of better understanding the biological etiology of SAD. There are several treatments available for SAD, and not all individuals respond to the first-line treatment of light therapy. Therefore, better understanding o the biology behind this disorder could lead to better treatment protocols that might reduce the likelihood of treatment failure and shorten time to remission by potentially avoiding ineffective treatment.

描述（由申请人提供）：季节性情感障碍（SAD）的特点是具有季节性模式的反复抑郁发作，最常发生在秋季和冬季。尽管 SAD 的潜在机制仍不清楚，但一种假设假设对日光季节变化的反应出现异常。抑郁症发作的常规冬季时间、生物学的季节性变化以及光疗法 (LT) 对 SAD 的益处都表明了这一点。 SAD 患者对光的反应减弱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所致，这些神经节细胞表达黑视蛋白并向生物钟传递有关白天长度的信息。这些细胞还驱动称为照明后瞳孔反应（PIPR）的瞳孔光反射的一部分，其中瞳孔在光偏移后收缩。研究发现，与正常小鼠相比，缺失黑视蛋白基因的小鼠 PIPR 降低。敏感性降低的黑视蛋白通路可以解释 SAD 的风险。为了支持这一假设，我们最近发现 SAD 患者黑视蛋白基因中特定序列变异的频率较高。我们现在将测试与健康对照相比，SAD 患者的 PIPR 是否减弱，以及以下其他假设。该提案的具体目标有三个： (1) 确定 SAD 患者的 PIPR 相对于非季节性、非抑郁对照组以及与有非季节性重度抑郁症病史的个体相比是否存在差异。我们将使用黑视蛋白最敏感的特定波长的蓝光。根据动物研究和我们的初步数据，我们预测，相对于没有抑郁病史的个体以及具有非季节性抑郁模式的个体，患有 SAD 的个体对蓝光的 PIPR 会减弱。 (2) 确定与对照组相比，患有 SAD 的个体在 PIPR 上是否随季节变化。 (3) 确定黑视蛋白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视蛋白驱动的 PIPR 是否因抑郁症诊断、抑郁发作的季节性模式、测量季节或黑视蛋白基因的序列变异而有所不同。我们的初步数据表明，患有 SAD 的人对蓝光的 PIPR 减弱。如果 SAD 对季节性日光减少的异常反应源于黑视蛋白细胞敏感性低，那么 PIPR 可能可以作为 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视蛋白介导的，黑视蛋白途径的遗传变异可能有望预测 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，并可能确定临床上有用的 SAD 风险标记。 公共卫生相关性：重度抑郁症是一种非常普遍、慢性且使人衰弱的心理健康问题，具有巨大的社会成本和巨大的经济负担。冬季季节性情感障碍 (SAD) 是复发性重度抑郁症的一种亚型，涉及严重的抑郁症状，从成年早期开始，大多数年份每年约 5 个月对家庭和工作场所产生不利影响。本提案旨在研究黑视蛋白通路在SAD中的作用，以期更好地了解SAD的生物学病因。有多种治疗 SAD 的方法，但并非所有个体都对光疗法的一线治疗有反应。因此，更好地了解这种疾病背后的生物学可能会导致更好的治疗方案，从而可能避免无效的治疗，从而降低治疗失败的可能性并缩短缓解时间。