The effects of gestational opioid exposure on the maternal brain, behavior and microbiome

阿片类药物使用障碍(OUD)是一种全球流行病，影响着高比例的育龄妇女。戏剧性的 1999-2014年间，孕妇的OUD增加了4倍，促进了阿片类药物的维持治疗 (OMT)，如丁丙诺啡(BUP)，以减轻与阿片类药物滥用相关的影响。BUP是混合的(部分 Mu受体激动剂/kappa受体拮抗剂)半合成OMT，在治疗后产生更好的婴儿结局 与其他口服避孕药(即美沙酮)相比，妊娠治疗。然而，BUP对妊娠的影响 人们对过渡到为人母的女性并没有很好的理解。内源性阿片类药物在 在母体大脑网络(MBN)内协调神经元适应，以成功地从 从未分娩的大脑到母体的大脑，以激励从大坝培育母体的行为。这是众所周知的 外源性阿片类药物在怀孕期间接触吗啡(全吗激动剂)可以改变内源性阿片类药物。 并扰乱了产妇保健。然而，人们对BUP的影响还存在认识上的差距。 在向母性转变期间的内源性阿片系统，从而对背景下的产妇护理行为的影响 在怀孕期间发生了性行为异常。拟议的研究旨在通过实施 评价BUP与吗啡对母鼠大脑、行为影响的动物模型 以及微生物群对后代的长期结果的影响。雌性大鼠将暴露于BUP 和/或吗啡在临床相关范例中从受孕前开始并持续到早期 产后。孕期BUP和吗啡暴露对神经化学和激活模式的影响 母亲大脑的变化将使用最先进的成像技术进行评估。我们还将评估 催产素作为一种潜在的干预措施在阿片类药物治疗中增加母子相互作用的有效性 并调查微生物群在暴露的后代的长期健康结果中的作用。 我们的提案将能够添加到人类关于功能连接改变的初步发现中 丁丙诺啡暴露的母亲通过使用“全(半)脑活动图”，这将使我们能够 同时照亮MBN几个脑区在细胞分辨率下的活动并比较模式 阿片类药物暴露和对照大坝之间的关系，并调查与母亲行为变化的关系。我们 预计围产期暴露于BUP会抑制神经元从厌恶的感觉转变为有益的感觉 幼崽是启动适当的母体行为所必需的，从而随后影响后代的存活。 阿片类药物流行的规模需要紧急应对，以促进妊娠期OUD的治疗 在已经被边缘化的人口中。我们希望推动关于阿片类药物后果的科学研究 在妊娠期使用/治疗，并将这些结果应用于临床知识，以改善公共健康 通过有效地翻译、实施和传播我们的科学研究成果。

Opioid use disorder (OUD) is a global epidemic affecting a high proportion of child-bearing women. The drastic 4-fold increase in OUD among pregnant women from 1999-2014 has promoted opioid maintenance therapies (OMT) such as buprenorphine (BUP) to mitigate effects associated with opioid abuse. BUP is a mixed (partial mu-receptor agonist/kappa-receptor antagonist) semi-synthetic OMT that produces better infant outcomes after gestational treatment as compared to other OMTs (i.e. methadone). However, effects of BUP on pregnant women transitioning to motherhood is not well understood. Endogenous opioids play a significant role in orchestrating neuronal adaptations within the maternal brain network (MBN) for the successful ‘switch’ from a nulliparous brain to a maternal brain to incentivize nurturing maternal behaviors from the dam. It is well known that exogenous opioid exposure to morphine (full mu-agonist) during gestation can alter the endogenous opioid system and disrupt maternal care. However, there is a knowledge gap about the effects of BUP on the endogenous opioid system during the transition to motherhood and thus on maternal care behavior in the context of OUD during pregnancy. The proposed studies aim to address this knowledge gap by implementing a translational rodent model to evaluate the effects of BUP compared to morphine on the maternal brain, behavior and the microbiome well as on the long-term outcome of the offspring. Female rats will be exposed to BUP and/or morphine in clinically relevant paradigms starting before conception and continued throughout early postpartum. Effects of gestational BUP and morphine exposure on neurochemical and activation pattern changes in the maternal brain will be evaluated using state of the art imaging techniques. We will also evaluate the effectiveness of oxytocin as a potential intervention to increase maternal-offspring interaction in opioid- exposed dams and investigate the role of the microbiome in the long-term health outcome of exposed offspring. Our proposal will be able to add to the preliminary human findings on altered functional connectivity in buprenorphine-exposed mothers by using ‘whole (half) brain activity mapping’ which will allow us to simultaneously illuminate activity at cellular resolution in several brain areas of the MBN and compare patterns between opioid-exposed and control dams and investigate associations with changes in maternal behaviors. We expect that perinatal exposure to BUP inhibits the neuronal ‘switch’ from aversive to rewarding perception of pups that is necessary to initiate appropriate maternal behavior thus subsequently influencing offspring survival. The scale of the opioid epidemic requires an urgent response in order to promote treatment of OUD in pregnancy within an already marginalized population. We hope to advance science on the consequences of opioid drug use/therapy during gestation and to apply these outcomes toward clinical knowledge to improve public health via effective translation, implementation, and dissemination of our scientific research findings.