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.

尽管有大量证据表明青少年酗酒与成人酒精依赖有很大不同 就饮酒习惯和治疗需求而言，很少有干预措施能够解决这些人的独特情况 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 增加对压力的敏感性，并促进饮酒以应对睡眠问题和焦虑。 19% 的 12 至 20 岁青少年表示过去一个月曾酗酒，30% 的人经常饮酒。在 除了学业困难、车祸甚至暴力等直接风险外，近一半的风险 青少年在一生中的某个阶段会与酒精依赖作斗争。为了减少酗酒，我们 首先需要改善睡眠并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在青春期小鼠中生成工作日-周末睡眠模式，以便建模 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 研究昼夜节律不同步和睡眠稳态如何影响睡眠的自我延续周期 青春期的干扰、压力和饮酒是最容易受到神经生物学影响的时期 改变潜在的成瘾，以及这个周期对成年饮酒的长期影响。接下来我们将进行测试 褪黑激素是否会重置内部时钟并作为从睡眠状态转换的有效系统信号 白天到夜间的生理模式，可以恢复睡眠并减少我们的压力和酒精摄入量 模型。在第一个目标中，昼夜节律表型笼将用于产生昼夜节律不同步，然后我们 将评估饮酒和睡眠模式、压力反应以及惩罚后的饮酒寻求 青春期雄性和雌性褪黑激素丰富的 C57BL/6 小鼠，我们将行为模式与 皮质酮和褪黑激素的有节奏释放，以及昼夜节律基因的有节奏表达 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， 让小鼠变老，然后在成年后测试相同的行为测量。在第二个目标中，我们将使用定时 限制睡眠以比自然醒来时间更早唤醒青春期小鼠并遵循相同的规则 评估如目标 1。我们建议，昼夜节律睡眠中断会通过扰乱睡眠来增加酒精摄入量。 睡眠，增加压力激活，并增加尽管受到惩罚仍酗酒工作的动力。在目标 3 中， 我们将通过研究这些因素如何进一步探讨酒精和昼夜节律睡眠中断对压力的影响 因素影响分子应力轴本身的活动。这将为 关于青少年酒精中昼夜节律睡眠系统与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 青少年并降低成年后患酒精使用障碍的风险。