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 催产素在出生时有几种适应性功能。实验 这两项令人兴奋的新研究都描述了催产素 神经保护作用的胎儿大脑在出生和最近的研究表明，正常 神经元周围网络（PNN）结构对于正确的认知和情感是必不可少的。 处理. PNN是包裹快速尖峰的细胞外基质复合物， 小清蛋白阳性中间神经元（PVI）并提供突触和网络稳定性。 虽然PNNs保护神经元免受氧化损伤，但PNNs本身是敏感的。 在发育过程中氧化应激，它们的降解与改变 interneuron电路，以及增强的小胶质细胞激活。重要的是，异常 PNN结构和中间神经元回路，以及过度的小胶质细胞激活， 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缓冲了胎儿大脑对 氧化应激，这表明这种激素可以保护发育中的PNN/PVIs。的 定期使用合成催产素（sOT; Pitocin）诱导或增加分娩，以及 产前剖宫产的普遍发生，改变了胎儿对催产素的暴露 在分娩过程中。然而，这些OT相关的出生操作如何影响 后代神经结构的发展在很大程度上仍然是未知的， 动物模型和人类。由于OT的神经保护作用，我们假设， 出生时OT相关操作改变氧化应激暴露和PNN形成。在 目的1，我们将检查出生时给予sOT对新生儿的剂量依赖性影响。 氧化应激和小胶质细胞活化，PVI和PNN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）如果产前剖宫产 分娩增加了胎儿氧化应激暴露和小胶质细胞活化， PVI和PNN的出生后发育，并改变后代的社会行为， B）如果在产前剖腹产后不久围产期给予OT可以挽救 预测神经和社会行为的变化。这项建议的目的是 确定是否与出生有关的干预措施，调节催产素信号， 递送改变特定的神经机制（PNN/PVI形成）。本研究的数据将 告知我们目前对神经结构正常发育的理解， 帮助评估用于操纵分娩过程的治疗方法。