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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要昼夜节律是与物质使用相关的脆弱因素。滥用药物会夹带和扰乱昼夜节律和节律紊乱的人容易患上药物滥用障碍，造成恶性循环。至少 20% 的美国人面临环境昼夜节律紊乱的风险 (CRD) 由于非标准轮班工作，包括晚班、夜班或轮班工作。轮班工人面临风险严重的负面健康结果，但女性由于更容易受到物质使用和与怀孕相关的其他负面结果。不仅是女轮班工人在怀孕期间会经历不良后果，但后代在出生时和以后的生活中也会受到影响。具体来说，轮班工人的后代的抑郁、危险行为和药物使用都会增加。重要的是，小鼠的产前 CRD (pCRD) 重现了这些风险，增加了不良妊娠结局以及成年后代的焦虑样行为。这些跨物种的一致结果表明环境 CRD 通过啮齿动物的光/暗周期转换是研究产前结果的一个很好的转化模型对人类的干扰。尽管药物滥用与轮班工作有关，但对于父母和后代来说，尚不清楚 pCRD 如何诱发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严重的物质使用样表型，药物偏好增加，可卡因的食物自我管理、强化和激励特性。另一方面，女性后代表现出相反的、快感缺失样表型，食物自我管理减少，可卡因自我管理减少可卡因的给药和强化特性，以及适应不良的过早习惯形成。自从滥用药物会影响昼夜节律，增加对药物的渴望和寻求，当预期药物时，增加 pCRD 后男性的奖励敏感性可能是由于昼夜节律的潜在变化所致。此外，我们实验室的证据表明，通过遗传改变与奖励相关的大脑区域的昼夜节律操纵，直接影响对可卡因的行为反应。这些数据表明 pCRD 扰乱昼夜节律运动活动的节律和成年期的奖励，也许是通过改变表达和节律性昼夜节律和昼夜节律调节基因。发育激素也是可能影响发育的潜在因素 pCRD 的性别特异性效应，因为在敏感期接触性腺激素会导致长期大脑和行为（组织）的变化。因此，本提案的假设是pCRD 与发育、组织激素相互作用，改变奖励节律、运动活动节律和奖赏和/或昼夜节律相关大脑区域的基因表达，导致物质使用样表型男性则缺乏快感，女性则缺乏快感。