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

青少年酒精暴露期间昼夜节律不同步对酒精成瘾的近期和长期风险的影响：睡眠稳态和压力信号的作用

• 批准号: 10673146
• 负责人: Danielle Gulick
• 金额: $ 37.81万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673146
• 关键词: 20 year old; Abstinence; Academy; Address; Adenosine; Adolescence; Adolescent; Adrenal Glands; Adult; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; American; Anxiety; Attenuated; Back; Beds; Behavior; Behavioral; Biological; Biological Clocks; C57BL/6 Mouse; Cellular Phone; Circadian Dysregulation; Circadian Rhythm Sleep Disorders; Circadian Rhythms; Circadian desynchrony; Circadian gene expression; Corticosterone; Corticotropin-Releasing Hormone Receptors; Cues; Delayed Sleep Phase Syndrome; Drowsiness; Electronics; Endorphins; Feeds; Female; Foundations; Goals; Habits; Health; Homeostasis; Hour; Hypothalamic structure; Intervention; Knowledge; Lead; Life; Light; Long-Term Effects; Male Adolescents; Measures; Melatonin; Modeling; Molecular; Mood Disorders; Motivation; Mus; Neurobiology; Pathway interactions; Pattern; Pediatrics; Periodicity; Phenotype; Physiological; Pituitary Gland; Predisposition; Prevalence; Protocols documentation; Punishment; Recommendation; Reporting; Research; Resistance; Rewards; Risk; Risk Reduction; Role; Schedule; Schools; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Stress; System; Teenagers; Testing; Time; United States; Violence; Work; addiction; adolescent alcohol abuse; adolescent alcohol effect; adolescent alcohol exposure; age group; alcohol availability; alcohol effect; alcohol reward; alcohol risk; alcohol seeking behavior; alcohol use disorder; alcohol use initiation; automobile accident; behavior measurement; binge drinking; biological adaptation to stress; circadian; cognitive function; cost; drinking; druggable target; falls; healthcare community; high school; improved; improved outcome; improvement on sleep; novel; reduced alcohol use; response; sex; sleep onset; sleep pattern; sleep quality; stem; stress reactivity; stressor; time use; twelfth grade; underage drinking

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.

尽管有足够的证据表明青少年酒精滥用与成人酒精依赖有很大不同 饮酒习惯和治疗需求的条款，很少有干预措施解决的独特情况 典型的青少年。超过一半的少年没有定期获得足够的睡眠。这种睡眠中断 增加对压力的敏感性，并促进对睡眠问题和焦虑的响应饮酒。 在12至20岁的12岁中，有19％的人报告了过去一个月的暴饮暴食，30％的人定期喝酒。在 除了直接存在学术困难，汽车事故甚至暴力之类的直接风险，其中几乎一半 青少年将在生活中的某个时刻与酒精依赖斗争。为了减少酒精滥用，我们 需要改善睡眠并减少导致青少年首先过度沉迷的压力源。我们有 为了建模 昼夜节律睡眠中断并研究随之而来的对压力和酒精摄入的影响。拟议的研究将 检查昼夜节律如何影响睡眠的自我持续周期 青春期的破坏，压力和饮酒是对神经生物学的最大脆弱时期 成瘾的基本变化以及该周期在成年期间对饮酒的长期影响。接下来，我们将测试 褪黑激素是否重置内部时钟并充当有效的系统提示 白天到夜间生理模式，可以恢复睡眠并减轻我们的压力和酒精摄入量 型号。在第一个目的中，昼夜节律笼子将用于产生昼夜节律的异位，然后我们 将评估饮酒和睡眠方式，压力反应性以及在惩罚后寻求酒精 青少年雄性和雌性褪黑激素的C57BL/6小鼠，我们将将行为模式与 皮质酮和褪黑激素的节奏释放以及昼夜节律的节奏表达 和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， 允许小鼠衰老，然后在成年期测试相同的行为度量。在第二个目标中，我们将使用定时 睡眠限制以比自然唤醒时间更早唤醒青春期小鼠，然后遵循相同的唤醒时间 与AIM 1一样的评估。我们建议昼夜节律的睡眠中断会通过破坏来增加酒精摄入量 尽管受到了惩罚，睡眠，增加压力激活以及增加饮酒的动力。在AIM 3中， 我们将通过研究如何进一步探索酒精和昼夜节律睡眠破坏对压力的影响 因素影响分子应力轴本身的活性。这将为 关于昼夜节律睡眠系统与青少年酒精中应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都可以减少酒精摄入量的潜力 在青少年中，并降低成年后期出现饮酒障碍的风险。