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