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

项目摘要/摘要 昼夜节律是与物质使用有关的一个脆弱因素。滥用毒品缠绕和破坏 昼夜节律和那些节律被打乱的人很容易患上药物使用障碍， 造成了恶性循环。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，包括晚班、夜班或轮班工作。倒班工人处于危险之中 造成严重的负面健康后果，但女性受影响尤其大，因为更容易患上 与怀孕相关的物质使用和其他负面后果。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在以后的生活中。 具体地说，在轮班工人的后代中，抑郁、危险行为和药物使用都会增加。 重要的是，小鼠的产前CRD(PCRD)概括了这些风险，增加了不良妊娠结局 以及成年后代的焦虑行为。这些跨物种的一致结果表明环境CRD 啮齿动物通过光/暗周期转换是研究产前结局的一个很好的转换模型 对人类的干扰。尽管物质使用与轮班工作有关，但在父母和子女中，这一点尚不清楚 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成年小鼠与物质使用相关的结果。我发现了一致的性别差异，男性 患有慢性阻塞性肺疾病的后代表现出深刻的类似药物使用的表型，并增加了药物偏好， 食物自我管理，增强和激励可卡因的特性。另一方面，雌性后代 表现出相反的，非享乐性的表型，食物自我给药减少，可卡因自我 给药和可卡因的强化特性，以及不适应的过早习惯的形成。自.以来 滥用药物牵涉到昼夜节律，增加了对药物的渴望和寻求，增加了 男性在pCRD后的奖赏敏感性可能是由于昼夜节律的潜在变化。此外, 我们实验室的证据表明，与奖赏相关的大脑区域的昼夜节律改变，通过基因 操纵，直接影响对可卡因的行为反应。这些数据表明pCRD扰乱了昼夜节律。 成年后运动活动和奖赏的节律，可能是通过改变 昼夜节律和昼夜节律调控基因。发育激素也是一个潜在的因素，可能影响 PCRD的性别特异性影响，因为在敏感期暴露于性腺激素会导致长期的 大脑和行为(组织)的变化。因此，这一提议的假设是pCRD 与发育和组织激素相互作用，改变奖励、运动活动和 奖赏和/或昼夜节律相关脑区的基因表达，导致小鼠出现物质使用样表型 雄性和雌性的非享乐性类似。

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.