DAT18-09 Maternal opioid exposure and executive function evaluation in the mouse

摘要 主题DAT 18 -09：阿片类药物及其拮抗剂对胎儿和新生儿大脑发育的影响 今天，使用阿片类药物的孕妇人数前所未有， 在子宫内接触这些药物的婴儿数量增加。医疗保健资源正在改善 这些新生儿的存活率，但我们对他们的长期预后知之甚少。的 少数跟踪长期结果的研究，人类的结果表明， 与执行功能、自我控制和认知有关的问题。除了滥用药物， 与吗啡或海洛因一样，美沙酮或丁丙诺啡的药物辅助治疗（MAT）是 稳定阿片类药物依赖母亲的护理标准。虽然MAT在限制 新生儿戒断综合征的严重程度和发生率，以改善新生儿的直接结局， 这些治疗仍然是阿片类药物，穿过胎盘到达发育中的胎儿， 后代的行为问题。在人类中，服用美沙酮和/或 丁丙诺啡在需要抑制控制的任务中具有认知缺陷和损伤， 计划性、适应性和短期记忆。虽然关于母体使用阿片类药物的人类数据 表明长期的执行功能缺陷，很少有啮齿动物的研究， 缺乏，没有专门检查执行功能。本申请旨在填补 这个研究缺口。 小胶质细胞，大脑的常驻免疫细胞，可能介导母体阿片类药物使用的不良反应 因为小胶质细胞对阿片类药物有反应，在神经发育中起着关键作用。 和行为。阿片类药物可通过TLR 4激活小胶质细胞，并刺激神经元凋亡。 释放细胞因子和趋化因子。抑制小胶质细胞或它们的炎症信号可以减少 人类和啮齿类动物对阿片类药物的行为反应。此外，母体阿片类药物暴露 降低了后代皮层树突的复杂性，这表明小胶质细胞介导的修剪可能 与行为表型有关。 因此，拟议的研究将检验母体阿片类药物暴露 药物辅助治疗会对后代的大脑和行为产生不利影响 通过TLR 4激活小胶质细胞。除了测试这个假设，一个额外的目标 该提案的目的是完善母体阿片类药物暴露的小鼠模型并建立基础 未来的研究将评估其他细胞和分子机制，并开始解决 潜在治疗干预的有效性。在三个目标中，我们将评估执行功能， 先进的操作性测试，并评估突触蛋白，棘密度和神经元小胶质细胞 使用免疫组织化学和共聚焦成像的相互作用。

Abstract Topic DAT18-09: Effects of Opioids and their Antagonists on Fetal and Neonatal Brain Development Today, there are unprecedented numbers of pregnant women using opioid drugs leading to a rise in the numbers of infants exposed to these drugs in utero. Healthcare resources are improving the survival rate of these neonates, but we know relatively little about their long-term prognosis. Of the few studies that track long-term outcomes, results in humans indicate consistent behavioral problems related to executive function, self-control, and cognition. In addition to drugs of abuse such as morphine or heroin, medication assisted treatment (MAT) with methadone or buprenorphine is the standard of care for stabilizing opioid dependent mothers. While MAT is effective in limiting the severity and incidence of neonatal abstinence syndrome to improve immediate neonatal outcomes, these treatments are still opioid drugs, cross the placenta to the developing fetus, and cause behavioral problems in the offspring. In humans, children born to mothers on methadone and/or buprenorphine have cognitive deficits and impairments in tasks that require inhibitory control, planning, adaptability, and short-term memory. While the human data on maternal opioid use indicate long-term executive function deficits, very few rodent studies have studied behavioral deficits and none specifically examine executive function. The present application is designed to fill that research gap. Microglia, the brain's resident immune cells, may mediate adverse effects of maternal opioid use on the brain because microglia respond to opioid drugs and play a critical role in neurodevelopment and behavior. Opioids can activate microglia through toll-like receptor 4 (TLR4) and stimulate the release of cytokines and chemokines. Inhibiting microglia or their inflammatory signals reduces the behavioral response to opioids, in humans and rodents. Furthermore, maternal opioid exposure decreases offspring cortical dendritic complexity, suggesting that microglial-mediated pruning may be involved in the behavioral phenotypes. Therefore, the proposed studies will test the hypothesis that maternal opioid exposure and medication-assisted treatment will adversely affect the offspring brain and behavior through activation of microglia via TLR4. In addition to testing this hypothesis, an additional goal of this proposal is to refine a mouse model of maternal opioid exposure and establish a foundation for future studies to evaluate additional cellular and molecular mechanisms and begin to address efficacy of potential therapeutic interventions. Across three aims, we will assess executive function with advanced operant testing, and evaluate synaptic proteins, spine density and neuron-microglia interactions using immunohistochemistry and confocal imaging.