Effects of circadian desynchrony during adolescent alcohol exposure on immediate and long-term risk of alcohol addiction: role of sleep homeostasis and stress signaling

尽管有充分的证据表明青少年酗酒与成人酗酒在以下方面有很大不同 在饮酒习惯和治疗需求方面，很少有干预措施针对老年人的独特情况 典型的青少年。超过一半的青少年经常睡眠不足。这种睡眠中断 增加对压力的敏感度，并推动酒精消费，以应对睡眠问题和焦虑。 在12到20岁的青少年中，19%的人报告在过去的一个月里酗酒，30%的人经常饮酒。在……里面 除了学习困难、车祸甚至暴力等迫在眉睫的风险外，几乎有一半的人 青少年会在他们一生中的某个时候与酒精依赖作斗争。为了减少酗酒，我们 首先需要改善睡眠，减少导致青少年过度沉迷的压力源。我们有 开发了一种新的方案来产生青春期小鼠的工作日-周末睡眠模式，以便建立 并研究其对压力和酒精摄入量的影响。拟议的研究将 检查昼夜节律去同步化和睡眠稳态如何影响睡眠的自我延续周期 青春期的精神分裂、压力和饮酒，这是神经生物学最脆弱的时期 改变潜在的成瘾，以及这个循环对成年后饮酒的长期影响。接下来，我们将测试 褪黑素，它重置内部时钟，并作为一个强有力的系统性信号，从 从白天到夜间的生理模式，可以恢复睡眠，减少压力和酒精摄入量 模特们。在第一个目标中，昼夜节律表型笼将被用来产生昼夜去同步化，然后我们 将评估酒精饮酒和睡眠模式，压力反应性，以及惩罚后的酒精寻求 青春期精通褪黑素的雄性和雌性C57BL/6小鼠，我们将把行为模式与 皮质酮和褪黑素的节律性释放以及昼夜节律基因的节律性表达 和促肾上腺皮质激素释放因子受体。在第二组中，我们将遵循相同的青少年协议， 让小鼠衰老，然后在成年后测试同样的行为指标。在第二个目标中，我们将使用Timed 睡眠限制使青春期小鼠比自然唤醒时间更早醒来，并遵循同样的规律 目标1中的评估。我们认为，昼夜节律睡眠中断会通过干扰 睡眠，增加压力激活，并增加不顾惩罚为酒精工作的动力。在《目标3》中， 我们将通过研究酒精和昼夜睡眠中断对压力的影响来进一步探索这些影响 影响分子应力轴活性的因素本身。这将为 青少年酒精昼夜节律睡眠系统与应激轴相互作用的认识 滥用，这些相互作用的长期影响，以及褪黑素都可以减少酒精摄入量 减少青少年酒精使用障碍的风险，并降低成年后出现酒精使用障碍的风险。

Despite ample evidence that adolescent alcohol abuse differs dramatically from adult alcohol dependence in terms of both drinking habits and treatment needs, few interventions address the unique circumstances of the typical teen. More than half of teenagers do not get enough sleep on a regular basis. This sleep disruption increases sensitivity to stress and drives alcohol consumption in response to both sleep problems and anxiety. 19% of 12- to 20-year-olds report binge drinking in the past month, and 30% drink alcohol on a regular basis. In addition to immediate risks such as academic difficulty, car accidents and even violence, almost half of these adolescents will struggle with alcohol dependence at some point in their lives. To reduce alcohol abuse, we need to improve sleep and reduce the stressors that lead adolescents to over-indulge in the first place. We have developed a novel protocol to generate a weekday-weekend sleep pattern in adolescent mice, in order to model circadian sleep disruption and study the ensuing effects on stress and alcohol intake. The proposed studies will examine how circadian desynchrony and sleep homeostasis impact the self-perpetuating cycle of sleep disruption, stress, and alcohol drinking in adolescence, the period of greatest vulnerability to the neurobiological changes underlying addiction, and the long-term effects of this cycle on drinking in adulthood. Next, we will test whether melatonin, which resets the internal clock and serves as a potent systemic cue for the switch from daylight to nighttime physiological patterns, can restore sleep and reduce both stress and alcohol intake in our models. In the first Aim, circadian phenotyping cages will be used to generate circadian desynchrony, then we will assess alcohol drinking and sleep patterns, stress reactivity, and alcohol seeking after punishment in adolescent male and female melatonin-proficient C57BL/6 mice, and we will correlate behavioral patterns with the rhythmic release of corticosterone and melatonin, as well as with the rhythmic expression of circadian genes and corticotropin releasing factor receptors. In a second group, we will follow the same adolescent protocol, allow mice to age, then test the same behavioral measures in adulthood. In the second Aim, we will use timed sleep restriction to awaken adolescent mice earlier than their natural wake-up time and follow the same assessments as in Aim 1. We propose that circadian sleep disruptions will increase alcohol intake by disrupting sleep, increasing stress activation, and increasing motivation to work for alcohol despite punishment. In Aim 3, we will further explore the effects of alcohol and circadian sleep disruption on stress by examining how these factors impact the activity of the molecular stress axis itself. This will provide an essential foundation of knowledge about the interactions between the circadian sleep system and the stress axis in adolescent alcohol abuse, the long-term effects of these interactions, and the potential for melatonin to both reduce alcohol intake in adolescents and to reduce the risk of developing alcohol use disorders later in adulthood.