An Examination of Oxytocin as a Neuroprotective Factor for the Development of Perineuronal Nets Using an Animal Model to Simulate Birth Interventions

使用动物模型模拟生育干预，检查催产素作为神经周围网络发育的神经保护因子

• 批准号: 9896185
• 负责人: Marcy A Kingsbury
• 金额: $ 24.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896185
• 关键词: ARHGEF5 gene; Acids; Affect; Animal Model; Anti-Inflammatory Agents; Antioxidants; Architecture; Atopobium vaginae; Behavioral; Binding; Birth; Brain; Buffers; Cesarean section; Cognitive; Complex; Data; Development; Dose; Electrophysiology (science); Emotional; Environment; Epilepsy; Equilibrium; Evaluation; Exposure to; Extracellular Matrix; Female; Fetus; Gene Expression; Genetic; Glutathione; Hormones; Human; Hyperactive behavior; Hypoxia; Hypoxic Brain Damage; Impaired cognition; Impairment; In Vitro; Induced Labor; Inflammation; Inflammatory; Injections; Interneurons; Intervention; Label; Labor augmentation; Lead; Link; Mediating; Mental disorders; Metabolic; Microglia; Mus; Neurodevelopmental Disorder; Neurons; Outcome; Oxidative Stress; Oxytocin; Oxytocin Receptor; Parvalbumins; Perinatal; Pitocin; Postpartum Period; Pregnant Women; Process; Reporting; Research; Resistance; Rodent Model; Role; Saline; Schizophrenia; Sensory; Signal Transduction; Social Behavior; Structure; Synapses; United States; Vagina; Vaginal delivery procedure; Woman; autism spectrum disorder; autistic behaviour; base; brain abnormalities; brain behavior; brain tissue; critical period; experience; experimental study; fetal; gamma-Aminobutyric Acid; in vivo; inhibitory neuron; male; method development; mouse model; neonatal encephalopathy; neural circuit; neurodevelopment; neuromechanism; neuron loss; neuroprotection; offspring; oxidative damage; postnatal; postnatal development; prairie vole; pregnant; prenatal exposure; relating to nervous system; social; stem; synaptic function

Abstract The hormone oxytocin has several adaptive functions at birth. The experiments proposed here stem from both exciting new research describing oxytocin's neuroprotective role for the fetal brain at birth and recent studies indicating that normal perineuronal net (PNN) architecture is essential for proper cognitive and emotional processing. PNNs are extracellular matrix complexes that enwrap fast-spiking, parvalbumin-positive interneurons (PVIs) and provide synaptic and network stability. While PNNs protect neurons against oxidative damage, PNNs themselves are sensitive to oxidative stress during development and their degradation is associated with altered interneuron circuitry, as well as enhanced microglial activation. Importantly, aberrant PNN structure and interneuron circuitry, as well as exaggerated microglial activation, are linked with neurodevelopmental disorders, psychiatric disorders and cognitive dysfunction. Interestingly, oxytocin signaling at birth buffers the fetal brain against oxidative stress, suggesting that this hormone may protect developing PNNs/PVIs. The regular use of synthetic oxytocin (sOT; Pitocin) to induce or augment labor, as well as the common occurrence of pre-labor cesarean sections, alter fetal exposure to oxytocin during delivery. However, how these OT-related birth manipulations affect the development of neural architecture of offspring remains largely unexplored in both animal models and humans. Because of OT's neuroprotective role, we hypothesize that OT-related manipulations at birth alter oxidative stress exposure and PNN formation. In Aim 1, we will examine the dose-dependent effects of sOT administration at birth on oxidative stress and microglial activation, postnatal development of PVIs and PNNs, and social behavior within offspring. In Aim 2, we will determine a) if a pre-labor cesarean delivery increases fetal oxidative stress exposure and microglial activation, disrupts postnatal development of PVIs and PNNs, and alters social behavior within offspring and b) if perinatal administration of OT shortly after a pre-labor C-section can rescue the predicted neural and social behavioral changes. The purpose of this proposal is to determine whether birth-related interventions that modulate oxytocin signaling during delivery alter a specific neural mechanism (PNN/PVI formation). Data from this study will inform our current understanding of the normal development of neural architecture and aid in the evaluation of treatments used to manipulate the birth process.

摘要 荷尔蒙催产素在出生时有几种适应功能。这些实验 这里提出的建议源于两项令人兴奋的新研究，描述了催产素 出生时胎儿大脑的神经保护作用和最近的研究表明正常 周围神经网络(PNN)的结构对于正确的认知和情感是必不可少的 正在处理。PNN是包裹快速尖峰的细胞外基质复合体， 小白蛋白阳性中间神经元(PVI)，并提供突触和网络的稳定性。 虽然PNNS保护神经元免受氧化损伤，但PNNS本身是敏感的 在发育过程中的氧化应激，它们的降解与改变有关 神经元间电路，以及增强的小胶质细胞激活。重要的是，反常 PNN结构和神经元间电路，以及夸大的小胶质细胞激活 与神经发育障碍、精神障碍和认知障碍有关 功能障碍。有趣的是，出生时的催产素信号会缓冲胎儿的大脑 氧化应激，提示这种激素可能保护发展中的PNNS/PVI。这个 经常使用合成催产素(催产素；催产素)来引产或增加分娩，以及 常见的产前剖宫产、胎儿宫内催产素暴露 在分娩过程中。然而，这些与催产期相关的生育操纵如何影响 子代神经结构的发育在很大程度上仍未被探索 动物模型和人类。由于OT的神经保护作用，我们假设 出生时与OT相关的操作改变了氧化应激暴露和PNN的形成。在……里面 目的1，我们将研究出生时给药的剂量依赖性效应。 氧化应激和小胶质细胞激活，PVI和PNNS的出生后发育，以及 后代的社会行为。在目标2中，我们将确定a)是否进行产前剖腹产 分娩增加了胎儿氧化应激暴露和小胶质细胞的激活，扰乱了 PVI和PNN的出生后发育，并改变后代和 B)如果在产前剖腹产后不久围产期使用催产素可以挽救 预测神经和社会行为的变化。这项建议的目的是 确定调节催产素信号的出生相关干预措施是否 分娩改变了特定的神经机制(PNN/PVI的形成)。这项研究的数据将 告诉我们目前对神经结构正常发展的理解 帮助评估用于操纵分娩过程的治疗方法。