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

 描述(申请人提供)：过量饮酒是一种重大的公共健康负担，在他们一生中的某个时候会影响30%的人，对肝脏有贡献 以及心血管疾病、肥胖症、糖尿病和癌症，每年的医疗保健成本为246亿美元，生产力损失为1613亿美元。即使在50%-70%的美国成年人中，适度的社交饮酒也与健康风险有关。许多人类研究一直表明，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后，昼夜节律的延迟也与更多的酒精使用和滥用有关。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，这可能会导致进一步的饮酒。中央昼夜节律起搏器调节昼夜节律的时间，但每天都受到固有的光敏视网膜神经节细胞(IpRGC)发出的光信号的调节。对啮齿动物的研究表明，酒精直接作用于中央昼夜节律起搏器，将昼夜节律的相移改变为光。然而，酒精对ipRGC对光反应的影响仍有待研究。这个应用程序回答了PA-12-177，它要求“在人类中进行机械学研究……以确定酒精如何干扰昼夜节律的重置，以响应环境刺激……最终目的是改善对酒精中毒的原因和治疗的理解”。我们建议使用一种新的可靠的光刺激技术，在轻度饮酒者(男32人，女32人)和重度饮酒者(男32人，女32人)中，测量急性和慢性酒精对人类ipRGC对光反应的影响。在一项受试者内、双盲、安慰剂对照、随机设计(26天方案)中，我们将评估基线以及醉酒剂量前后的ipRGC反应(与安慰剂对照)。我们还将研究ipRGC的反应如何预测基线的昼夜节律时间，以及通过测量微弱的光褪黑素开始的昼夜相移到明亮的光。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剂量酒精的主观反应之间的关系。目的1是确定大量饮酒(与少量饮酒相比)在多大程度上改变光诱发的ipRGC反应和昼夜节律。目标2是确定醉人剂量的酒精(与安慰剂相比)在多大程度上改变了ipRGC的反应和昼夜节律向光的转变。目标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反应与昼夜节律、情绪、睡眠、奖励功能和饮酒之间的关系。这项拟议的研究将提供一个亟需的机械性理解，以了解酒精如何影响人类的光俘获和昼夜节律，以及这些如何影响情绪、睡眠和奖励功能，进而预测酒精的使用/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.