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

项目总结/摘要 昼夜节律是与物质使用相关的脆弱性因素。滥用药物会夹带和破坏 昼夜节律和那些节律被破坏的人容易发生物质使用障碍， 形成恶性循环。至少20%的美国人面临环境昼夜节律紊乱的风险 (CRD)由于工作非标准班次，包括晚上，夜间或轮班工作。轮班工人面临风险 对健康产生重大负面影响，但女性受到的影响尤其严重，因为她们更容易受到 物质使用和与怀孕相关的其他负面结果。不仅女性轮班工人 在怀孕期间会经历不良后果，但后代也会受到影响，无论是在出生时还是以后的生活中。 具体来说，倒班工人的后代抑郁、危险行为和物质使用都增加了。 重要的是，小鼠的产前CRD（pCRD）重现了这些风险，增加了不良妊娠结局 和类似焦虑的行为。这些跨物种的一致结果表明环境CRD 通过啮齿类动物的光/暗周期转换是一个很好的翻译模型，用于研究产前的结果， 人类的分裂。虽然物质使用与轮班工作有关，但在父母和后代中， pCRD如何导致物质使用的长期风险。在我的初步实验中，我测量了各种 pCRD成年小鼠的物质使用相关结果。我发现男性存在一致的性别差异， 患有CRD的母鼠的后代表现出明显的物质使用样表型，药物偏好增加， 食物自我管理，可卡因的强化和激励特性。另一方面，雌性后代 表现出相反的，快感缺失样表型，减少食物自我管理，可卡因自我管理， 可卡因的服用和强化特性，以及适应不良的过早习惯形成。以来 滥用药物会影响昼夜节律，增加对药物的渴望和寻求， pCRD后男性的奖赏敏感性可能是由于昼夜节律的潜在变化。此外，本发明还提供了一种方法， 来自我们实验室的证据表明，通过遗传， 操纵，直接影响可卡因的行为反应。这些数据表明，pCRD扰乱昼夜节律 在成年期的运动活动和奖励的节奏，也许通过改变表达和节奏， 昼夜节律和昼夜节律调节基因。发育激素也是一个潜在的因素， pCRD的性别特异性效应，因为在敏感期暴露于性腺激素会诱导长期 改变大脑和行为（组织）。因此，该提议的假设是pCRD 与发育、组织激素相互作用，改变奖赏、运动活动节律， 基因表达在奖励和/或昼夜节律相关的大脑区域，导致物质使用样表型， 男性和女性的快感缺乏样。

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.