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.

抽象的 催产素在出生时具有多种自适应功能。实验 这里提出的源于描述催产素的新研究 出生时胎儿大脑的神经保护作用，最近的研究表明正常 会内神经元网（PNN）结构对于适当的认知和情感是必不可少的 加工。 PNN是细胞外矩阵复合物，可快速加速， 白蛋白阳性阳性中间神经元（PVI）并提供突触和网络稳定性。 PNNS保护神经元免受氧化损伤，而PNN本身是敏感的 发育过程中的氧化应激和降解与改变有关 内神经元电路，以及增强的小胶质细胞激活。重要的是，异常 PNN结构和间神经元电路以及夸张的小胶质激活是 与神经发育障碍，精神疾病和认知有关 功能障碍。有趣的是，催产素信号在出生缓冲的胎儿大脑反对 氧化应激，表明这种激素可以保护发展中的PNN/PVI。这 定期使用合成催产素（SOT; pitocin）诱导或增强劳动 前剖宫产前的常见发生，改变胎儿暴露于催产素 在交货期间。但是，这些与OT相关的出生操纵如何影响 后代神经建筑的发展在很大程度上尚未探索 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相关的操作会改变氧化应激暴露和PNN形成。在 AIM 1，我们将检查SOT给药在出生时的剂量依赖性影响 氧化应激和小胶质激活，PVI和PNN的产后发育以及 后代内的社会行为。在AIM 2中，我们将确定a）是否剖腹产 递送增加胎儿氧化应激暴露和小胶质细胞激活，破坏 PVI和PNN的产后发展，并改变后代内的社会行为 b）如果在劳动剖腹产剖腹产后不久对OT进行围产期给药可以挽救 预测神经和社会行为变化。该提议的目的是 确定是否调节催产素信号的干预措施是否在 递送改变了特定的神经机制（PNN/PVI形成）。这项研究的数据将 告知我们当前对神经架构正常发展的理解和 帮助评估用于操纵出生过程的治疗方法。