Mechanisms of prenatal opioid exposure on brain and behavior

摘要 阿片类药物过量死亡和阿片类药物使用障碍 (OUD) 的发展与 在美国，有问题的阿片类药物使用模式已达到危机水平。孕妇经常患有 OUD 接受美沙酮或丁丙诺啡 (BUP) 的 OUD (MOUD) 药物治疗，以减轻严重的健康状况 OUD 对母亲及其新生儿的影响。然而，越来越多的证据表明，母亲阿片类药物 治疗与异常影响后代大脑和行为的发育缺陷有关。然而， 根本机制仍然很大程度上未知。母亲接触阿片类药物可能会影响早期谱系和命运 通过作用于神经上表达的阿片受体，对中枢神经系统中的神经元和神经胶质细胞做出决定 干祖细胞（NSPC），但这方面存在知识空白。我们假设母亲阿片类药物 暴露于 BUP 管理会改变胚胎神经发生，从而导致神经发育异常 中皮质多巴胺通路，导致注意力缺陷多动障碍（ADHD）样行为 后遗症具有性别依赖性。这一假设将在母体阿片类药物的新型小鼠模型中得到检验 模拟 OUD 药物管理护理标准的暴露。三个具体目标是 提出：1）确定母体阿片类药物引起的大脑发育异常的细胞机制 在后代中，2）确定阿片类药物改变的中皮层发育与异常之间的关系 后代的行为，3) 确定母体阿片类药物暴露影响的分子机制 胚胎 NSPC 功能的影响这项综合研究采用了生化、遗传学和药理学 体外细胞和体内动物模型的操作；结果将通过分子评估， 细胞、神经解剖学和行为分析。破译孕产妇影响的潜在机制 阿片类药物暴露对 NSPC、大脑结构和行为的影响将增进我们对母体阿片类药物的了解 暴露后代的大脑和行为异常，为识别创新铺平道路 开发新疗法或预防策略以对抗阿片类药物对健康影响的目标 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.