Brandt M J V, Kosmeijer C M, Achterberg E J M, de Theije C G M, Nijboer C H
Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital, Utrecht University, Lundlaan 6, 3584 EA, Utrecht, the Netherlands.
Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 2, 3584 CM, Utrecht, the Netherlands.
Brain Behav Immun Health. 2024 Jul 5;40:100817. doi: 10.1016/j.bbih.2024.100817. eCollection 2024 Oct.
Extreme preterm birth-associated adversities are a major risk factor for aberrant brain development, known as encephalopathy of prematurity (EoP), which can lead to long-term neurodevelopmental impairments. Although progress in clinical care for preterm infants has markedly improved perinatal outcomes, there are currently no curative treatment options available to combat EoP. EoP has a multifactorial etiology, including but not limited to pre- or postnatal immune activation and oxygen fluctuations. Elucidating the underlying mechanisms of EoP and determining the efficacy of potential therapies relies on valid, clinically translatable experimental models that reflect the neurodevelopmental and pathophysiological hallmarks of EoP. Here, we expand on our double-hit rat model that can be used to study EoP disease mechanisms and therapeutic options in a preclinical setting. Pregnant Wistar dams were intraperitoneally injected with 10 μg/kg LPS on embryonic day (E)20 and offspring was subjected to hypoxia (140 min, 8% O) at postnatal day 4. Rats exposed to fetal inflammation and postnatal hypoxia (FIPH) showed neurodevelopmental impairments, such as reduced nest-seeking ability, ultrasonic vocalizations, social engagement, and working memory, and increased anxiety and sensitivity. Impairments in myelination, oligodendrocyte maturation and interneuron development were examined as hallmarks for EoP, in different layers and coordinates of the cortex using histological and molecular techniques. Myelin density and complexity was decreased in the cortex, which partially coincided with a decrease in mature oligodendrocytes. Furthermore, interneuron populations (GAD67+ and PVALB+) were affected. To determine if the timing of inducing fetal inflammation affected the severity of EoP hallmarks in the cortex, multiple timepoints of fetal inflammation were compared. Inflammation at E20 combined with postnatal hypoxia gave the most severe EoP phenotype in the cortex. In conclusion, we present a double-hit rat model which displays various behavioral, anatomical and molecular hallmarks of EoP, including diffuse white matter injury. This double-hit model can be used to investigate pathophysiological mechanisms and potential therapies for EoP.
极早早产相关的不良情况是大脑发育异常的主要危险因素，即早产儿脑病（EoP），这可能导致长期神经发育障碍。尽管早产儿临床护理的进展显著改善了围产期结局，但目前尚无治愈性治疗方案来对抗EoP。EoP有多种病因，包括但不限于产前或产后免疫激活以及氧波动。阐明EoP的潜在机制并确定潜在疗法的疗效依赖于有效的、可临床转化的实验模型，这些模型能够反映EoP的神经发育和病理生理特征。在此，我们扩展了我们的双打击大鼠模型，该模型可用于在临床前环境中研究EoP疾病机制和治疗方案。在胚胎期（E）20，给怀孕的Wistar母鼠腹腔注射10μg/kg脂多糖（LPS），并在出生后第4天将子代置于低氧环境（140分钟，8%氧气）中。暴露于胎儿炎症和产后低氧（FIPH）的大鼠表现出神经发育障碍，如寻窝能力降低、超声发声、社交参与和工作记忆受损，以及焦虑和敏感性增加。使用组织学和分子技术，在皮质的不同层和坐标中检查髓鞘形成、少突胶质细胞成熟和中间神经元发育的损伤情况，将其作为EoP的特征。皮质中的髓鞘密度和复杂性降低，这部分与成熟少突胶质细胞的减少相一致。此外，中间神经元群体（GAD67+和PVALB+）受到影响。为了确定诱导胎儿炎症的时间是否会影响皮质中EoP特征的严重程度，比较了胎儿炎症的多个时间点。E20时的炎症与产后低氧相结合，在皮质中产生了最严重的EoP表型。总之，我们提出了一种双打击大鼠模型，该模型表现出EoP的各种行为、解剖和分子特征，包括弥漫性白质损伤。这种双打击模型可用于研究EoP的病理生理机制和潜在疗法。
