Investigating the long-term effects of prenatal circadian rhythm disruption on substance use-related disorders

调查产前昼夜节律紊乱对物质使用相关疾病的长期影响

• 批准号: 10569027
• 负责人: Lauren Marie DePoy
• 金额: $ 13.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569027
• 关键词: Adult; Adult Children; Adverse event; Affect; American; Anhedonia; Behavior; Behavioral; Birth; Brain; Brain region; Chromatin; Chronic; Circadian Dysregulation; Circadian Rhythms; Cocaine; Darkness; Data; Development; Disease; Dissociation; Dopamine; Drug Exposure; Early identification; Environmental Risk Factor; Estradiol; Exposure to; FDA approved; Female; Food; Four Core Genotypes; Gene Expression; Genes; Gonadal Hormones; Habits; Health; Hormones; Human; Life; Light; Link; Long-Term Effects; Longevity; Measures; Mental Depression; Modeling; Molecular; Motivation; Motor Activity; Mus; Nucleus Accumbens; Outcome; Outcome Study; Ovary; Overdose; Pacemakers; Parents; Pathway interactions; Periodicity; Pharmaceutical Preparations; Phase; Phenotype; Population; Populations at Risk; Pregnancy; Prevention; Property; Rewards; Risk; Risk Behaviors; Rodent; Rotation; Self Administration; Sex Differences; Sleep; Substance Use Disorder; Testis; Therapeutic; Time; Tissues; Vulnerable Populations; adverse outcome; adverse pregnancy outcome; aged; anxiety-like behavior; behavioral phenotyping; behavioral response; circadian; cocaine self-administration; conditioned place preference; craving; driving behavior; drug of abuse; evidence base; experimental study; genetic manipulation; genotypic sex; male; new therapeutic target; novel; offspring; preference; premature; prenatal; reward anticipation; sex; shift work; stimulant abuse; substance use; substance use treatment; suprachiasmatic nucleus; targeted treatment; transcriptome sequencing; translational model

Project Summary/Abstract Circadian rhythms are a vulnerability factor associated with substance use. Drugs of abuse entrain and disrupt circadian rhythms and those with disrupted rhythms are vulnerable to developing substance use disorders, creating a vicious cycle. At least 20% of Americans are at risk for environmental circadian rhythm disruptions (CRD) due to working nonstandard shifts, including evening, night or rotating shift work. Shift workers are at risk for substantial negative health outcomes, but females are particularly affected due to greater vulnerability for substance use and additional negative outcomes associated with pregnancy. Not only do female shift workers experience adverse outcomes during pregnancy, but offspring are also affected, both at birth and later in life. Specifically, depression, risky behavior and substance use are all increased in the offspring of shift workers. Importantly, prenatal CRD (pCRD) in mice recapitulates these risks, increasing adverse pregnancy outcomes and anxiety-like behavior in adult offspring. These consistent results across species suggest environmental CRD via light/dark cycle shifting in rodents is a good translational model for studying the outcomes of prenatal disruptions in humans. Although substance use is associated with shift work, in parents and offspring, it is unclear how pCRD induces long-term risk for substance use. In my preliminary experiments, I measured a variety of substance use-related outcomes in adult mice with pCRD. I found consistent sex differences where male offspring of dams with CRD showed a profound substance use-like phenotype, with increased drug preference, food self-administration, reinforcing and motivational properties of cocaine. On the other hand, female offspring showed an opposite, anhedonic-like phenotype with decreased food self-administration, cocaine self- administration and the reinforcing properties of cocaine, as well as maladaptive premature habit formation. Since drugs of abuse entrain circadian rhythms, increasing craving and seeking when drugs are anticipated, increased reward sensitivity in males after pCRD could be due to underlying changes in circadian rhythms. In addition, evidence from our lab suggests that altered circadian rhythms in reward-related brain regions, through genetic manipulations, directly effect behavioral responses to cocaine. These data suggest that pCRD disrupts circadian rhythms in locomotor activity and reward in adulthood, perhaps by altering the expression and rhythmicity of circadian and circadian-regulated genes. Developmental hormones are also a potential factor that could impact sex-specific effects of pCRD since exposure to gonadal hormones during sensitive periods induces long-term changes to the brain and behavior (organizational). Therefore, the hypothesis of this proposal is that pCRD interacts with developmental, organizational hormones to alter rhythms in reward, locomotor activity rhythms and gene expression in reward- and/or circadian-related brain regions, leading to a substance use-like phenotype in males and anhedonic-like in females.

项目摘要/摘要 昼夜节律是与药物使用相关的脆弱因素。滥用药物被夹住并破坏 昼夜节律和有障碍的节奏很容易受到发展药物使用障碍的影响， 创建一个恶性循环。至少有20％的美国人有昼夜节律中断的风险 （CRD）由于工作非标准班次，包括晚上，夜晚或旋转班次工作。轮班工人处于危险之中 对于大量的负面健康结果，但由于更大的脆弱性，女性尤其受到影响 用途和与怀孕有关的其他负面结果。不仅女性转班工人 怀孕期间经历不良后果，但后代在出生时和以后的生活中也受到影响。 具体而言，在轮班工人的后代，抑郁症，危险行为和药物使用都增加了。 重要的是，小鼠的产前CRD（PCRD）概括了这些风险，增加了不良怀孕的结果 和成人后代的焦虑行为。这些物种之间的这些一致的结果表明环境CRD 通过光/黑暗周期转移啮齿动物是研究产前结果的良好翻译模型 人类的破坏。尽管药物使用与转移工作相关，但在父母和后代中，尚不清楚 PCRD如何诱导使用物质的长期风险。在我的初步实验中，我测量了各种各样的 PCRD成年小鼠中与物质使用相关的结果。我发现男性的性别差异一致 用CRD的大坝的后代显示出强烈的物质使用样表型，药物偏好增加， 食物自我给药，可卡因的增强和动机特性。另一方面，女性后代 表现出相反的，类似厌氧的表型，食物自我给药降低，可卡因自我 可卡因的给药和增强特性以及适应不良的早产习惯形成。自从 虐待药物中吸引了昼夜节律，增加何时预期药物，增加毒品，增加 PCRD后男性的奖励灵敏度可能是由于昼夜节律的基本变化所致。此外， 我们实验室的证据表明，与奖励相关的大脑区域中的昼夜节律改变了，通过遗传 操纵，直接影响对可卡因的行为反应。这些数据表明PCRD破坏了昼夜节律 运动和奖励在成年期的节奏，也许是通过改变的表达和节奏性 昼夜节律和昼夜节律调节的基因。发育激素也是可能影响的潜在因素 PCRD的性别特异性自敏感时期暴露于性腺激素以来会诱导长期 改变大脑和行为（组织）。因此，该提议的假设是PCRD 与发展性的组织激素相互作用，以改变奖励，运动活动的节奏和 奖励 - 和/或昼夜节律相关的大脑区域中的基因表达，导致物质使用样表型 雄性和类似女性的anhedonic。