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，青少年酗酒与成人酒精依赖有很大的不同， 就饮酒习惯和治疗需求而言，很少有干预措施解决这些人的独特情况。 典型的青少年超过一半的青少年没有得到足够的睡眠。这种睡眠中断 增加对压力的敏感性，并在应对睡眠问题和焦虑时推动酒精消费。 19%的12至20岁的年轻人报告在过去一个月内狂饮，30%的人定期饮酒。在 除了学业困难、车祸甚至暴力等直接风险外， 青少年在其一生中的某个阶段将与酒精依赖作斗争。为了减少酗酒，我们 首先，我们需要改善睡眠，减少导致青少年过度放纵的压力源。我们有 开发了一种新的方案，在青春期小鼠中产生工作日-周末睡眠模式， 昼夜睡眠中断，并研究随之而来的压力和酒精摄入量的影响。拟议的研究将 研究昼夜节律和睡眠稳态如何影响睡眠的自我延续周期 青春期的破坏、压力和饮酒，这是最容易受到神经生物学影响的时期。 改变潜在的成瘾，以及这种周期对成年饮酒的长期影响。接下来，我们将测试 褪黑激素，它重置内部时钟，并作为一个强大的系统提示，从开关， 白天到夜间的生理模式，可以恢复睡眠，减少我们的压力和酒精摄入量， 模型在第一个目标中，昼夜表型笼将用于产生昼夜节律，然后我们 将评估饮酒和睡眠模式，压力反应，以及惩罚后的酒精寻求， 青少年男性和女性褪黑激素熟练的C57 BL/6小鼠，我们将相关的行为模式与 皮质酮和褪黑激素的节律性释放，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， 让老鼠变老，然后在成年后测试同样的行为指标。在第二个目标中，我们将使用定时 睡眠限制唤醒青春期小鼠早于他们的自然醒来时间，并遵循相同的 目标1中的评估。我们认为，昼夜睡眠中断会增加酒精摄入量， 睡眠，增加压力激活，增加为酒精工作的动机，尽管受到惩罚。在目标3中， 我们将进一步探讨酒精和昼夜睡眠中断对压力的影响， 这些因素影响分子应力轴本身的活性。这将提供一个重要的基础， 关于青少年饮酒的昼夜睡眠系统和压力轴之间相互作用的知识 滥用，这些相互作用的长期影响，以及褪黑激素减少酒精摄入量的潜力 在青少年中，并减少成年后患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.