Mechanisms of prenatal opioid exposure on brain and behavior

摘要 阿片类药物过量死亡和阿片使用障碍(OUD)的发展与 在美国，有问题的阿片类药物使用模式已经达到了危机水平。妊娠合并尿毒症的孕妇经常 接受美沙酮或丁丙诺啡(BUP)的药物治疗以减轻严重的健康 胎儿宫内发育对母亲及其新生儿的影响。然而，越来越多的证据表明，母体阿片类药物 治疗与发育缺陷有关，这些缺陷会异常地影响后代的大脑和行为。然而， 潜在的机制在很大程度上仍不清楚。母亲接触阿片类药物可能影响早期血统和命运 作用于神经上表达的阿片受体对中枢神经系统神经元和神经胶质细胞的决定 干细胞前体细胞(NSPC)，但在这方面存在知识空白。我们假设母体阿片类药物 暴露于BUP管理改变胚胎神经发生，这导致异常发育 中皮质多巴胺通路，导致注意缺陷多动障碍(ADHD)样行为 后遗症以性别依赖的方式出现。这一假说将在母体阿片类药物的新小鼠模型中得到验证 暴露于模拟OUD药物管理的护理标准。三个具体目标是 建议：1)确定母体阿片类药物导致大脑发育异常的细胞机制 在子代中，2)确定阿片类药物改变的中皮质发育与畸形的关系 子代的行为，以及3)确定母体阿片类药物暴露影响的分子机制 胚胎NSPC功能的研究。这项综合研究运用了生化、遗传学和药理学。 在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。破译母体感染影响的潜在机制 NSPC、大脑结构和行为上的阿片类药物暴露将促进我们对母体阿片类药物的了解 暴露于子代的大脑和行为异常，为鉴定创新能力铺平道路 制定新的治疗或预防战略以对抗阿片类药物对健康的影响的目标 在怀孕期间。

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.