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

DAT18-09 母体阿片类药物暴露和小鼠执行功能评估

基本信息

批准号：
9814868
负责人：
TERESA M REYES
金额：
$ 24.08万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9814868
关键词：
Address Adolescence Adverse effects Affect Animals Attention Attention deficit hyperactivity disorder Behavior Behavioral Brain Brain region Buprenorphine Cells Child Cognition Cognitive deficits Development Diagnosis Evaluation Executive Dysfunction Exposure to Fetal Development Foundations Future Goals Healthcare Heroin Human Hyperactive behavior Immune Immunohistochemistry Impaired cognition Impairment Incidence Infant Inflammatory Link LoxP-flanked allele Mediating Methadone Microglia Modeling Molecular Morphine Mothers Mus Neonatal Abstinence Syndrome Neurons Opiate Addiction Opioid Outcome Pathway interactions Perinatal Pharmaceutical Preparations Phenotype Placenta Play Pregnant Women Problem behavior Proteins Research Resources Rodent Role Self-control as a personality trait Severities Shapes Short-Term Memory Signal Transduction Survival Rate Synapses TLR4 gene Testing Therapeutic Intervention Vertebral column behavioral response behavioral study brain behavior chemokine clinically relevant confocal imaging cytokine density design drug of abuse emotion regulation executive function fetal human data improved in utero maternal opioid use medication-assisted treatment mouse model mu opioid receptors neonatal brain neonatal outcome neonate neurodevelopment offspring opioid exposure opioid use outcome forecast pre-clinical prenatal prescription opioid standard of care synaptic pruning

项目摘要

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.

抽象的主题 DAT18-09：阿片类药物及其拮抗剂对胎儿和新生儿大脑发育的影响如今，使用阿片类药物的孕妇数量空前，导致了在子宫内接触这些药物的婴儿数量增加。医疗资源日趋完善这些新生儿的存活率，但我们对其长期预后知之甚少。的少数跟踪长期结果的研究，人类的结果表明一致的行为与执行功能、自我控制和认知相关的问题。除了滥用药物之外，与吗啡或海洛因一样，美沙酮或丁丙诺啡药物辅助治疗 (MAT) 是稳定阿片类药物依赖母亲的护理标准。虽然 MAT 可有效限制新生儿戒断综合征的严重程度和发生率，以改善新生儿的即时结局，这些治疗方法仍然是阿片类药物，会穿过胎盘到达发育中的胎儿，并导致后代的行为问题。在人类中，母亲服用美沙酮和/或丁丙诺啡在需要抑制控制的任务中具有认知缺陷和障碍，计划、适应性和短期记忆。虽然关于母亲阿片类药物使用的人类数据表明长期执行功能缺陷，很少有啮齿动物研究研究行为缺陷，并且没有专门检查执行功能。本申请旨在填补研究差距。小胶质细胞是大脑的常驻免疫细胞，可能会介导母亲使用阿片类药物的不良影响影响大脑，因为小胶质细胞对阿片类药物有反应，并在神经发育中发挥关键作用和行为。阿片类药物可以通过 Toll 样受体 4 (TLR4) 激活小胶质细胞，并刺激细胞因子和趋化因子的释放。抑制小胶质细胞或其炎症信号可减少人类和啮齿动物对阿片类药物的行为反应。此外，母亲接触阿片类药物降低后代皮质树突的复杂性，表明小胶质细胞介导的修剪可能参与行为表型。因此，拟议的研究将检验母亲阿片类药物暴露的假设药物辅助治疗会对后代的大脑和行为产生不利影响通过 TLR4 激活小胶质细胞。除了检验这个假设之外，还有一个目标该提案的目的是完善母亲阿片类药物暴露的小鼠模型并建立基础以便未来的研究评估其他细胞和分子机制并开始解决潜在治疗干预措施的功效。我们将通过三个目标评估执行功能通过先进的操作测试，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进行相互作用。