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）的发展与阿片类药物滥用增加有关。 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 接受美沙酮或丁丙诺啡（BUP）治疗OUD（MOUD），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， 治疗与异常影响后代大脑和行为的发育缺陷有关。然而 基本的机制仍然是未知的。母体阿片类药物暴露可能影响早期谱系和命运 中枢神经系统中的神经元和神经胶质细胞通过作用于神经元上表达的阿片受体来决定 干祖细胞（NSPCs），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管理会改变胚胎神经发生，导致胚胎神经细胞的异常发育。 中皮层多巴胺通路，引起注意缺陷多动障碍（ADHD）样行为 以性别依赖的方式出现后遗症。这一假设将在母体阿片样物质的新型小鼠模型中进行测试。 暴露，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诱导的异常脑发育的细胞机制 在后代中，2）确定阿片样物质改变的中皮层发育和异常的 行为在后代中，和3）确定母体阿片类药物暴露影响的分子机制 对胚胎NSPC功能的影响这项综合研究采用了生物化学，遗传学和药理学 在体外细胞和体内动物模型中操作;并且结果将通过分子， 细胞、神经解剖学和行为分析。解读孕产妇死亡影响的潜在机制 阿片类药物暴露对NSPCs，脑结构和行为的影响将促进我们对母体阿片类药物的认识 暴露在大脑和行为异常的后代，并铺平了道路，以识别创新 制定新的治疗方法或预防战略以消除类阿片对健康的影响的目标 孕期

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.