The Effect of Alcohol on Retinal Photic Signaling to the Human Circadian System

 描述（由申请人提供）：过度饮酒是一个重大的公共卫生负担，影响30%的人口在他们生命中的某个时候，有助于肝脏 以及心血管疾病、肥胖、糖尿病和癌症，每年在医疗保健方面花费246亿美元，在生产力方面损失1613亿美元。即使是50%-70%的美国成年人适度的社交饮酒也与健康风险有关。许多对人类的研究一致表明，昼夜节律的延迟与更多的酒精使用和滥用有关，即使在控制了青春期发育，年龄，性别，种族，社会经济地位和教育水平等因素之后。昼夜节律的延迟，即使是很小的延迟，也会对情绪，睡眠和奖励功能产生负面影响，这可能会推动进一步的酒精消费。中枢昼夜节律起搏器调节昼夜节律的定时，但每天通过来自内在光敏视网膜神经节细胞（ipRGC）的光信号进行调节。对啮齿动物的研究表明，酒精直接作用于中枢昼夜节律起搏器，改变了昼夜节律对光线的相移。然而，酒精对ipRGC对光响应的影响仍有待研究。这个应用程序回答PA-12-177，其中要求“在人类中的机械研究......以确定酒精如何干扰生物钟对环境刺激的反应。最终目标是提高对酗酒原因和治疗方法的认识”。我们建议测量急性和慢性酒精对人类ipRGC对光反应的影响，在64名轻度（32名男性，32名女性）和64名重度（32名男性，32名女性）社交饮酒者中使用新颖可靠的光刺激技术。在受试者内、双盲、安慰剂对照、随机化设计（26天方案）中，我们将评估在基线处以及在中毒剂量的酒精之前和之后的ipRGC应答（相对于安慰剂）。我们还将研究ipRGC响应如何预测基线昼夜节律定时，以及通过测量昏暗光褪黑激素起始来向明亮光的昼夜节律相移。最后，我们将评估基线ipRGC活动和昼夜节律与基线情绪，睡眠质量和奖励功能以及对急性酒精剂量的主观反应的关系。目的1是确定重度饮酒模式（与轻度饮酒相比）改变光诱发的ipRGC反应和昼夜节律定时的程度。目的2是确定酒精中毒剂量（与安慰剂相比）改变ipRGC反应和昼夜节律对光的转变的程度。目的3是确定ipRGC反应在多大程度上预测轻度和重度饮酒者的昼夜节律。在探索性目标中，我们将评估：（1）酒精对ipRGC反应和昼夜节律的影响是否与性别（男性、女性）和对酒精的主观反应有关，以及（2）基线ipRGC反应、昼夜节律之间的关系、情绪、睡眠、奖励功能和酒精使用。拟议的研究将提供一个迫切需要的机制，了解酒精如何影响人类的光诱导和昼夜节律，以及这些如何影响情绪，睡眠和奖励功能，这反过来又可以预测酒精的使用/滥用。

 DESCRIPTION (provided by applicant): Excessive alcohol consumption is a significant public health burden that affects 30% of the population at some point in their lives, contributes to liver and cardiovascular disease, obesity, diabetes and cancer, and costs $24.6 billion in health care and $161.3 billion in lost productivity annually. Even the moderate social drinking in 50%-70% of US adults is associated with health risks. Many studies in humans have consistently shown that a delay in circadian timing is associated with more alcohol use and abuse, even after controlling for factors such as pubertal development, age, sex, race, socioeconomic status, and educational level. Delays in circadian timing, even small ones, negatively affect mood, sleep, and reward function, which can drive further alcohol consumption. The central circadian pacemaker regulates the timing of circadian rhythms, but is adjusted daily by light signaling from intrinsically photosensitive retinal ganglion cells (ipRGCs). Research in rodents has demonstrated that alcohol acts directly on the central circadian pacemaker, altering circadian phase shifts to light. However, the effect of alcohol on ipRGC responses to light remains to be investigated. This application answers PA-12-177, which calls for "mechanistic studies in humans...to determine how alcohol interferes in circadian resetting in response to environmental stimuli...with ultimate goal of improved understanding of causes and treatments for alcoholism". We propose to measure the effects of acute and chronic alcohol on ipRGC responses to light in humans, using a novel and reliable photostimulating technology in 64 light (32 men, 32 women) and 64 heavy (32 men, 32 women) social drinkers. In a within-subjects, double-blind, placebo-controlled, randomized design (26 day protocol), we will assess ipRGC responses at baseline and before and after an intoxicating dose of alcohol (vs. placebo). We will also examine how ipRGC responses predict baseline circadian timing, and circadian phase shifts to bright light by measuring the dim light melatonin onset. Finally, we will assess how baseline ipRGC activity and circadian timing relate to baseline mood, sleep quality and reward function, and to the subjective response to an acute dose of alcohol. Aim 1 is to determine the extent to which a heavy alcohol drinking pattern (vs. lighter drinking) alters light-evoked ipRGC responses and circadian timing. Aim 2 is to determine the extent to which an intoxicating dose of alcohol (vs. placebo) alters ipRGC responses and circadian shifts to light. Aim 3 is to determine the extent to which ipRGC responses predict circadian timing in light and heavy drinkers. In exploratory aims, we will assess: (1) if the effect of alcohol on ipRGC responses and circadian timing are associated with sex (men, women) and subjective responses to alcohol and (2) the relationships among baseline ipRGC responses, circadian timing, mood, sleep, reward function, and alcohol use. The proposed research will provide a critically needed mechanistic understanding of how alcohol impacts photoentrainment and circadian timing in humans, and how these influence mood, sleep, and reward function, which in turn can predict alcohol use/misuse.