Mechanisms of prenatal opioid exposure on brain and behavior

产前阿片类药物暴露对大脑和行为的机制

• 批准号: 10657323
• 负责人: Kathryn A. Cunningham
• 金额: $ 63.14万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657323
• 关键词: Abbreviations; Affect; Animal Model; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biochemical; Biological; Brain; Brain region; Buprenorphine; Cells; Central Nervous System; Chronology; Clinical; Clinical Management; Clozapine; Defect; Dependovirus; Development; Disease Management; Dopamine; Embryo; Exposure to; Genetic; Glucuronides; Health; Immunohistochemistry; In Vitro; Knowledge; Link; MAP Kinase Gene; Male Adolescents; Maternal-fetal medicine; Medial; Medication Management; Methadone; Microdialysis; Mitogen-Activated Protein Kinases; Molecular; Mothers; Motor Activity; Mus; Neuroanatomy; Neurobiology; Neuroglia; Neurons; Neurophysiology - biologic function; Newborn Infant; Nociception; Opioid; Opioid Receptor; Opioid agonist; Outcome; Outcome Study; Oxides; Oxycodone; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Polymerase Chain Reaction; Prefrontal Cortex; Pregnancy; Pregnant Women; Prevalence; Prevention strategy; Proliferating; Reaction Time; Reporting; Research Personnel; Rewards; Safety; Scientist; Structure; Substance Use Disorder; Testing; Tyrosine 3-Monooxygenase; United States; Ventral Tegmental Area; adolescent offspring; brain abnormalities; buprenorphine treatment; cognitive control; combat; designer receptors exclusively activated by designer drugs; enhanced green fluorescent protein; experience; fetal opioid exposure; genetic analysis; health of the mother; human male; in utero; in vivo; innovation; male; medication for opioid use disorder; motor control; mouse model; neonate; nerve stem cell; neural; neurodevelopment; neurogenesis; novel; novel therapeutic intervention; object recognition; offspring; opioid exposure; opioid mortality; opioid use; opioid use disorder; opioid use in pregnancy; overdose death; pharmacologic; pre-clinical; pregnant; sex; small hairpin RNA; standard of care; stem; stem cell biology; stem cell function; stem cells; translational model

ABSTRACT Opioid overdose deaths and the development of opioid use disorder (OUD) associated with the rise in problematic opioid use patterns have reached crisis levels in the United States. Pregnant women with OUD often undergo medication for OUD (MOUD) with methadone or buprenorphine (BUP) to reduce the severe health effects of OUD in mothers and their newborns. However, there is increasing evidence that maternal opioid treatment is associated with developmental defects that aberrantly affect offspring brain and behavior. Yet, the underlying mechanisms remain largely unknown. Maternal opioid exposure may influence early lineage and fate decisions for neurons and glia in the central nervous system by acting on opioid receptors expressed on neural stem progenitor cells (NSPCs), but knowledge gaps exist in this regard. We hypothesize that maternal opioid exposure with BUP management alters embryonic neurogenesis, which leads to aberrant development of the mesocortical dopamine pathway, causing attention deficit hyperactivity disorder (ADHD)-like behavioral sequelae in a sex-dependent manner. This hypothesis will be tested in a novel murine model of maternal opioid exposure that mimics the standard of care for medication management of OUD. Three specific aims are proposed: 1) determine cellular mechanisms underlying maternal opioid-induced abnormal brain development in offspring, 2) determine the relationship between opioid-altered mesocortical development and aberrant behavior in offspring, and 3) determine molecular mechanisms underlying effects of maternal opioid exposure on embryonic NSPC function. This integrative study employs biochemical, genetic, and pharmacological manipulations in both in vitro cell and in vivo animal models; and the outcomes will be evaluated by molecular, cellular, neuroanatomical and behavioral analyses. Deciphering mechanisms underlying the impact of maternal opioid exposure on NSPCs, brain structure and behavior will advance our knowledge of maternal opioid exposure on brain and behavior abnormalities of offspring and pave the way toward identification of innovative targets for the development of new treatments or preventive strategies to combat the health effects of opioids during pregnancy.

抽象的 阿片类药物过量死亡以及阿片类药物使用障碍（OUD）的发展 有问题的阿片类药物使用模式在美国达到了危机水平。经常患有Oud的孕妇 用美沙酮或丁丙诺啡（BUP）对OUD（MOUD）进行药物治疗，以降低严重的健康 Oud对母亲及其新生儿的影响。但是，有越来越多的证据表明孕产妇阿片类药物 治疗与异常影响后代大脑和行为的发育缺陷有关。但是， 潜在的机制在很大程度上尚不清楚。产妇阿片类药物的暴露可能会影响早期血统和命运 通过在神经上表达的阿片受体作用，对中枢神经系统中神经元和神经胶质的决定 茎祖细胞（NSPC），但在这方面存在知识差距。我们假设孕产妇阿片类药物 与BUP管理接触的暴露会改变胚胎神经发生，从而导致异常发展 中皮层多巴胺途径，导致注意力缺陷多动障碍（ADHD）类似行为 后遗症以性别依赖性方式。该假设将在母体阿片类药物的新型鼠模型中进行检验 模仿OUD药物管理的护理标准的暴露。三个具体目标是 提议：1）确定孕产妇阿片类药物诱导的异常脑发育的细胞机制 在后代，2）确定阿片类药物改变的中皮质发育与异常之间的关系 后代的行为和3）确定母体阿片类药物暴露的分子机制 在胚胎NSPC功能上。这项综合研究采用生化，遗传和药理 体外细胞和体内动物模型中的操作；结果将通过分子评估 细胞，神经解剖学和行为分析。孕产妇影响的基础机制 NSPC，大脑结构和行为上的阿片类药物暴露将提高我们对孕产妇阿片类药物的了解 对后代的大脑和行为异常的暴露，并为识别创新的方式铺平了道路 开发新疗法或预防策略的目标，以应对阿片类药物的健康影响 怀孕期间。