Mechanisms of Hypoxia-Mediated Disturbances in Cerebral Maturation in a Fetal Ovine Model of Maternal Sleep Apnea

母体睡眠呼吸暂停胎羊模型中缺氧介导的大脑成熟障碍的机制

• 批准号: 10608612
• 负责人: Stephen Arthur Back
• 金额: $ 64.58万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608612
• 关键词: AMPA Receptors; Action Potentials; Acute; Adolescent; Adverse effects; Affect; Agonist; Air; Apnea; Behavioral; Brain; Brain region; Cell Death; Cellular Morphology; Cerebrum; Chemosensitization; Childhood; Chronic; Clinical Research; Data; Dendrites; Development; Diffusion Magnetic Resonance Imaging; Electrophysiology (science); Exposure to; Fetal Sheep; Fetal Tissues; Fetus; Fire - disasters; Frequencies; Future; Gestational Age; Glutamates; Growth; Hippocampus; Histologic; Hour; Hypoxemia; Hypoxia; Impairment; In Vitro; Infant Development; Inflammation; Learning; Long-Term Potentiation; Magnetic Resonance Imaging; Maternal complication; Measurement; Mediating; Memory; Memory impairment; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; Near-Infrared Spectroscopy; Neuroglia; Neurologic; Neurons; Outcome; Oxygen; Pathology; Pattern; Pre-Clinical Model; Predisposition; Pregnancy; Pregnant Women; Pregnant sheep; Reproducibility; Reproducibility of Results; Risk; Role; Shapes; Sleep Apnea Syndromes; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Third Pregnancy Trimester; Tissues; Twin Multiple Birth; Vertebral column; awake; behavioral study; brain based; brain volume; cerebral oxygenation; clinically relevant; density; disability; efficacy evaluation; fetal; fetal brain injury; fetus hypoxia; gray matter; hippocampal pyramidal neuron; improved; in utero; in vivo; maternal risk; mind control; morphometry; myelination; neural circuit; neurobehavioral; neurodevelopment; neuron loss; neurotransmission; novel; novel therapeutics; postnatal; pre-clinical; prenatal exposure; prevent; response; sheep model; tissue oxygenation; white matter; white matter injury

Project Summary Although sleep apnea arising from sleep-disordered breathing commonly occurs during pregnancy, the cumulative impact of brief repetitive episodes of maternal intermittent hypoxia (IHx) on fetal brain development is unknown. We have developed a novel clinically relevant model of maternal IHx, which reproducibly results in fetal systemic IHx early in the third trimester. The fetal hippocampus appears to be particularly sensitive to maternal IHx, which chronically disrupts neuronal activity and cellular mechanisms of learning and memory. Our over-riding hypothesis is that maternal IHx globally disrupts fetal cerebral development and results in persistent changes in postnatal learning and memory. In aim 1, we will first employ near infrared spectroscopy to define cerebral tissue hypoxemia in awake fetuses subjected to maternal IHx in utero. We will next determine the susceptibility of the fetal hippocampus to cell death, inflammation and white matter injury. We will also determine the impact of maternal IHx on disturbances in maturation of neuronal dendrites and spine density, which shape behaviorally important neural circuits, which regulate synaptic plasticity and neurotransmission during development. Complementary electrophysiological studies will determine the functional effects of IHx on synaptic transmission, long-term synaptic potentiation (LTP) and intrinsic excitability of hippocampal neurons to fire action potentials; which are all key cellular mechanisms that mediate learning and memory in vivo. Aim 2 will employ complementary advanced MRI and morphometric approaches to analyze the relative susceptibility of hippocampal-related brain regions to fetal IHx, which could inform future clinical studies by defining the global impact of maternal IHx on key brain regions required for optimal neurodevelopment and circuit formation. We will determine the spectrum of regional disturbances in fetal brain growth and maturation, cell death, inflammation and myelination and provide a quantitative analysis of differences in fetal brain volume differences. In aim 3, mechanistic fetal hippocampal studies will test the hypothesis that enhancing hippocampal synaptic transmission at CA3-CA1 synapses will reverse maternal IHx-mediated disturbances in fetal hippocampal synaptic plasticity, which underlie the developmental maturation of cellular mechanisms of learning and memory. We will determine in 3.1 the contribution of disturbances in AMPA and NMDA receptor subunit composition and expression levels to disturbances in glutamatergic synaptic transmission and LTP. In 3.2, we will determine the efficacy of an allosteric AMPA receptor agonist (ampakine) to strengthen synaptic transmission and plasticity in vitro. In 3.3, We will undertake pioneering neurobehavioral studies to determine if disrupted fetal hippocampal synaptic plasticity results in persistent hippocampal learning and memory deficits in juvenile lambs. Our long-term objectives are to define mechanisms through which maternal IHx disrupts fetal cerebral maturation and develop strategies to mitigate pregnancy-associated complications of maternal IHx on brain development, which may improve learning and memory.

项目概要 虽然睡眠呼吸障碍引起的睡眠呼吸暂停通常发生在怀孕期间，但 母亲间歇性缺氧（IHx）短暂重复发作对胎儿大脑发育的累积影响 未知。我们开发了一种新型的临床相关的孕产妇 IHx 模型，该模型可重复地导致 妊娠晚期胎儿全身性 IHx。胎儿海马体似乎对 母体 IHx，长期破坏神经元活动以及学习和记忆的细胞机制。我们的 最重要的假设是，母亲的 IHx 会全面扰乱胎儿的大脑发育，并导致持续的 产后学习和记忆的变化。在目标 1 中，我们将首先采用近红外光谱来定义 在子宫内接受母体 IHx 的清醒胎儿脑组织低氧血症。接下来我们将确定 胎儿海马对细胞死亡、炎症和白质损伤的易感性。我们还将确定 母亲 IHx 对神经元树突成熟和脊柱密度干扰的影响，这些影响 行为重要的神经回路，在过程中调节突触可塑性和神经传递 发展。补充电生理学研究将确定 IHx 对突触的功能影响 传输、长时程突触增强 (LTP) 和海马神经元对发射动作的内在兴奋性 潜力；这些都是介导体内学习和记忆的关键细胞机制。目标 2 将雇用 补充先进的 MRI 和形态测量方法来分析相对敏感性 海马相关的大脑区域与胎儿 IHx 相关，这可以通过定义全局 IHx 为未来的临床研究提供信息 母亲 IHx 对最佳神经发育和回路形成所需的关键大脑区域的影响。我们 将确定胎儿大脑生长和成熟、细胞死亡、炎症的区域紊乱范围 和髓鞘形成，并提供胎儿脑容量差异的定量分析。在目标 3 中， 胎儿海马机制研究将检验增强海马突触传递的假设 CA3-CA1 突触将逆转母体 IHx 介导的胎儿海马突触可塑性紊乱， 这是学习和记忆细胞机制发育成熟的基础。我们将确定 3.1 AMPA和NMDA受体亚基组成和表达水平紊乱的贡献 谷氨酸能突触传递和 LTP 的紊乱。在 3.2 中，我们将确定 变构 AMPA 受体激动剂（ampakine）可在体外增强突触传递和可塑性。在3.3中， 我们将进行开创性的神经行为研究，以确定胎儿海马突触是否受到破坏 可塑性导致幼年羔羊的海马体学习和记忆持续缺陷。我们的长期 目标是确定母亲 IHx 破坏胎儿大脑成熟和发育的机制 减轻孕产妇 IHx 对大脑发育的妊娠相关并发症的策略，这可能 改善学习和记忆。